**Meet the editor**

Dr. Juan Manuel Mejia-Arangure was born in Nayarit, Mexico. He received a Medical Doctor degree by the Universidad Nacional Autonoma de Mexico (UNAM). Afterwards he obtained MSc Sociomedical in the area of Epidemiology and in 2004 his PhD degree, with thesis: "Molecular epidemiology of childhood acute leukemias. An assessment of a causal model, interaction of

three factors: susceptibility, exposition and vulnerable time", for which he obtained Acknowledgement of Merit. Dr. Mejia-Arangure is member of Mexican and international societies including: Sistema Nacional de Investigadores, Academia Mexicana de Pediatria, Agrupacion Mexicana para el Estudio de la Hematologia, American Society of Hematology, the Society of Epidemiologic Research and the International Society for Environmental Epidemiology. He wrote 71 scientific articles and 13 book chapters and the present is his second book as Editor.

Contents

**Preface IX**

**Section 1 Hypothesis on the Etiology of ALL 1**

**Leukemia in Children 3** Juan Manuel Mejía-Aranguré

**Section 2 Pathophysiology of ALL 41**

Chapter 1 **Model for Identifying the Etiology of Acute Lymphoblastic**

Chapter 2 **Infectious Etiology of Childhood Acute Lymphoblastic Leukemia, Hypotheses and Evidence 19**

Chapter 3 **Pathophysiology of Acute Lymphoblastic Leukemia 43**

Chapter 5 **Adult T-Cell Leukemia/Lymphoma (ATL): Pathogenesis,**

Chapter 4 **Multi-Role of Cancer Stem Cell in Children Acute**

**Lymphoblastic Leukemia 75**

**Treatment and Prognosis 87** Shoko Kobayashi and Shigeki Iwasaki

Hong and Jie Zhang

Abigail Morales-Sánchez and Ezequiel M. Fuentes-Pananá

L. E. Figuera, A. M. Puebla-Pérez and J. R. García-González

M. P. Gallegos-Arreola, C. Borjas-Gutiérrez, G. M. Zúñiga-González,

Dong-qing Wang, Hai-tao Zhu, Yan-fang Liu, Rui-gen Yin, Liang Zhao, Zhi-jian Zhang, Zhao-liang Su, Yan-Zhu, Hui-qun Lu, Juan

## Contents

**Preface XIII**


#### **Section 3 Epidemiology of ALL 113**

Mejía-Aranguré

Chapter 6 **Etiological Research of Childhood Acute Leukemia with Cluster and Clustering Analysis 115** David Aldebarán Duarte-Rodríguez, Richard J.Q. McNally, Juan Carlos Núñez-Enríquez, Arturo Fajardo-Gutiérrez and Juan Manuel

Chapter 13 **Acute Lymphoblastic Leukemia (ALL) Philadelphia Positive**

**Principles of ALL Therapy) 297** Alicia Enrico and Jorge Milone

Chapter 14 **Invasive Fungal Infections in ALL Patients 317**

Kropshofer

**(Ph1) (Incidence Classifications, Prognostic Factor in ALL**

Contents **VII**

Roman Crazzolara, Adrian Kneer, Bernhard Meister and Gabriele


Chapter 13 **Acute Lymphoblastic Leukemia (ALL) Philadelphia Positive (Ph1) (Incidence Classifications, Prognostic Factor in ALL Principles of ALL Therapy) 297** Alicia Enrico and Jorge Milone

**Section 3 Epidemiology of ALL 113**

**VI** Contents

Mejía-Aranguré

Fajardo Gutiérrez

**and Clustering Analysis 115**

**Leukemia: A Review 145**

**Epidemiological Evidence 171**

**Lymphoblastic Leukemia 193**

Jorge Milone and Enrico Alicia

**Leukemia 277**

Mejía-Aranguré

Manuel Mejía-Aranguré

**Section 4 Prognostic of ALL 191**

Chapter 6 **Etiological Research of Childhood Acute Leukemia with Cluster**

Chapter 7 **Sociodemographic and Birth Characteristics in Infant Acute**

Chapter 8 **Infection During the First Year of Life and Acute Leukemia:**

Chapter 9 **Genetic Markers in the Prognosis of Childhood Acute**

Aguiar and Marco Antonio Leyva-Vázquez

Chapter 12 **Alterations of Nutritional Status in Childhood Acute**

David Aldebarán Duarte-Rodríguez, Richard J.Q. McNally, Juan Carlos Núñez-Enríquez, Arturo Fajardo-Gutiérrez and Juan Manuel

ML Pérez-Saldivar, JM Mejía-Aranguré, A Rangel-López and A

Janet Flores-Lujano, Juan Carlos Núñez-Enríquez, Angélica Rangel-López, David Aldebarán-Duarte, Arturo Fajardo-Gutiérrez and Juan

M.R. Juárez-Velázquez, C. Salas-Labadía, A. Reyes-León, M.P. Navarrete-Meneses, E.M. Fuentes-Pananá and P. Pérez-Vera

Jorge Organista-Nava, Yazmín Gómez-Gómez, Berenice Illades-

Alejandra Maldonado-Alcázar, Juan Carlos Núñez-Enríquez, Carlos Alberto García-Ruiz, Arturo Fajardo-Gutierrez and Juan Manuel

Chapter 10 **Survival of Patients with Acute Lymphoblastic Leukemia 237**

Chapter 11 **Bone Marrow Transplantation (BMT) in Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) 265**

Chapter 14 **Invasive Fungal Infections in ALL Patients 317** Roman Crazzolara, Adrian Kneer, Bernhard Meister and Gabriele Kropshofer

Preface

in the IMSS.

Clinical Epidemiology of Acute Lymphoblastic Leukemia: From the Molecules to the Clinic, is a book which has the goal of introducing the reader into the principal advances in the molecular biology of acute lymphoblastic leukemia (ALL) with application to the clinic.

There are four sections in the book. The first section is about the hypothesis on the etiology of ALL; two chapters were selected at this point. The model for identifying the etiology of ALL is my personnel viewpoint about the etiology of All, mainly in children. I believe that all cancer in children would have a similar behavior in its etiology, however my principal work as researcher during the last twenty years lies on the etiology of ALL in children,

In the second section the pathophysiology of ALL is described in three interesting articles. Epidemiology of ALL is mentioned in the third section where the review of different topics

Finally where reference is specially made to the participation of molecular rearrangements in the prognostic of ALL, in different countries like Mexico, the molecular diagnostic is not done in all the hospitals that attend children with ALL. It is important that the entire policy marker understands the importance that all patients would be diagnosed with the tools that increased the possibility of a better answer to the treatment. I decided to include malnutri‐ tion in this section because in undeveloped countries like Mexico malnutrition would ex‐ plain the high mortality of ALL, specially in children; however in other parts of the world malnutrition is not an important prognostic factor in the survival of children with ALL.

In the last year the development of the molecular biology has contributed in the advance of the survival of patients with ALL. However, current epidemiological findings have not been able to fully explain the etiology of the ALL. If this is a mystery we need to claim God for an answer, after all "He revealeth the deep and secret things: he knoweth what is in the dark‐

Today the patients with ALL are treated better than in the past however, today we cannot prevent the development of the disease. The cure of ALL increases the family's and patients´ hope, which is great. However if we can prevent the disease we will reduce the parents´ and

I thank all the contributors, many of whom are long-time friends and co-workers. Others are colleagues with whom I have collaborated, or learned from in the literature. Particular thanks go to Arturo Fajardo who has provide me with invaluable guidance over my years

therefore the hypothesis centers specially on this group of disease.

we want to work with in the future is showed to detail.

ness, and the light dwelleth with him" (Daniel 2:22).

patient´s broken heart when children are diagnosed with ALL.

## Preface

Clinical Epidemiology of Acute Lymphoblastic Leukemia: From the Molecules to the Clinic, is a book which has the goal of introducing the reader into the principal advances in the molecular biology of acute lymphoblastic leukemia (ALL) with application to the clinic.

There are four sections in the book. The first section is about the hypothesis on the etiology of ALL; two chapters were selected at this point. The model for identifying the etiology of ALL is my personnel viewpoint about the etiology of All, mainly in children. I believe that all cancer in children would have a similar behavior in its etiology, however my principal work as researcher during the last twenty years lies on the etiology of ALL in children, therefore the hypothesis centers specially on this group of disease.

In the second section the pathophysiology of ALL is described in three interesting articles. Epidemiology of ALL is mentioned in the third section where the review of different topics we want to work with in the future is showed to detail.

Finally where reference is specially made to the participation of molecular rearrangements in the prognostic of ALL, in different countries like Mexico, the molecular diagnostic is not done in all the hospitals that attend children with ALL. It is important that the entire policy marker understands the importance that all patients would be diagnosed with the tools that increased the possibility of a better answer to the treatment. I decided to include malnutri‐ tion in this section because in undeveloped countries like Mexico malnutrition would ex‐ plain the high mortality of ALL, specially in children; however in other parts of the world malnutrition is not an important prognostic factor in the survival of children with ALL.

In the last year the development of the molecular biology has contributed in the advance of the survival of patients with ALL. However, current epidemiological findings have not been able to fully explain the etiology of the ALL. If this is a mystery we need to claim God for an answer, after all "He revealeth the deep and secret things: he knoweth what is in the dark‐ ness, and the light dwelleth with him" (Daniel 2:22).

Today the patients with ALL are treated better than in the past however, today we cannot prevent the development of the disease. The cure of ALL increases the family's and patients´ hope, which is great. However if we can prevent the disease we will reduce the parents´ and patient´s broken heart when children are diagnosed with ALL.

I thank all the contributors, many of whom are long-time friends and co-workers. Others are colleagues with whom I have collaborated, or learned from in the literature. Particular thanks go to Arturo Fajardo who has provide me with invaluable guidance over my years in the IMSS.

#### X Preface

I dedicate this book to my wife (Norma Luque) and my son (Yurian Mejia) who are my in‐ spiration and the principal motif of my life.

#### **Dr. Juan Manuel Mejia-Arangure**

**Section 1**

**Hypothesis on the Etiology of ALL**

Pediatric Hospital, Centro Médico Nacional "Siglo XXI", Mexico **Hypothesis on the Etiology of ALL**

I dedicate this book to my wife (Norma Luque) and my son (Yurian Mejia) who are my in‐

**Dr. Juan Manuel Mejia-Arangure**

Mexico

Pediatric Hospital, Centro Médico Nacional "Siglo XXI",

spiration and the principal motif of my life.

X Preface

**Chapter 1**

**Model for Identifying the Etiology of Acute**

The incidence of ALL varies throughout the world; however, there is a greater frequency of the disease in those countries with a higher socio-economic level [1], with the exception that a higher frequency of ALL has been reported for some Hispanic cities [2]—cities that gener‐ ally are considered to have a lower standard of living. The highest incidence of ALL has

It is accepted that ALL is the result of the interaction, which occurs at a specific moment of life, between environmental factors and susceptibility to the disease [4]. The theories con‐ cerning the origin of this illness have been focussed fundamentally on the B-cell precursors of ALL [1]. The most important of these theories was proposed by Greaves and Kinlen; sev‐ eral more recent variations, such as the adrenal theory and infective lymphoid recovery hy‐

The theory of Greaves and that of Kinlen have been discussed in one of the chapters in this book. One of the limitations of the theory of Greaves is that it has not been possible to dem‐ onstrate it empirically. In his theory, Greaves argues that some cases of the pre-B ALL ob‐ served in the peak age of 2 to 5 years could be associated with an aberrant immune response displayed by an immature immune system. The early exposition to common infectious agents are required for the proper maturation of the immune system, lack of these exposi‐ tions results in aberrant responses when children are finally in contact with the agent When follow-up studies were carried out in order to evaluate whether children who suffered infec‐ tions during the first months of life had a greater risk of leukemia, it was not possible to demonstrate any such correlation. When kindergarten registries were used as information source, it was also not possible to demonstrate that there was an association with B-cell pre‐ cursors of ALL, or in a specific manner in which ALL appears between two and five years of

and reproduction in any medium, provided the original work is properly cited.

© 2013 Mejía-Aranguré; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Lymphoblastic Leukemia in Children**

Additional information is available at the end of the chapter

been reported for Costa Rica and for Mexico City [3].

pothesis have attempted to include these theories [5-8].

Juan Manuel Mejía-Aranguré

http://dx.doi.org/10.5772/52716

**1. Introduction**

## **Chapter 1**

## **Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children**

Juan Manuel Mejía-Aranguré

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52716

## **1. Introduction**

The incidence of ALL varies throughout the world; however, there is a greater frequency of the disease in those countries with a higher socio-economic level [1], with the exception that a higher frequency of ALL has been reported for some Hispanic cities [2]—cities that gener‐ ally are considered to have a lower standard of living. The highest incidence of ALL has been reported for Costa Rica and for Mexico City [3].

It is accepted that ALL is the result of the interaction, which occurs at a specific moment of life, between environmental factors and susceptibility to the disease [4]. The theories con‐ cerning the origin of this illness have been focussed fundamentally on the B-cell precursors of ALL [1]. The most important of these theories was proposed by Greaves and Kinlen; sev‐ eral more recent variations, such as the adrenal theory and infective lymphoid recovery hy‐ pothesis have attempted to include these theories [5-8].

The theory of Greaves and that of Kinlen have been discussed in one of the chapters in this book. One of the limitations of the theory of Greaves is that it has not been possible to dem‐ onstrate it empirically. In his theory, Greaves argues that some cases of the pre-B ALL ob‐ served in the peak age of 2 to 5 years could be associated with an aberrant immune response displayed by an immature immune system. The early exposition to common infectious agents are required for the proper maturation of the immune system, lack of these exposi‐ tions results in aberrant responses when children are finally in contact with the agent When follow-up studies were carried out in order to evaluate whether children who suffered infec‐ tions during the first months of life had a greater risk of leukemia, it was not possible to demonstrate any such correlation. When kindergarten registries were used as information source, it was also not possible to demonstrate that there was an association with B-cell pre‐ cursors of ALL, or in a specific manner in which ALL appears between two and five years of

© 2013 Mejía-Aranguré; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

age [9,10]. In addition, data are emerging from epidemiological databases that the idea of early infection being a protective factor for ALL originated due to a bias (non-differential misclassification) [11] and that, in reality, no such association exists. At any rate, determina‐ tion of whether a child suffered from different infections during the first year of life is ex‐ tremely difficult; for this reason, the empirical reference will need to be improved in order to lend greater support to this hypothesis.

One of the limitations in trying to identify the association between environmental factors and the development of ALL is that not taken into account is the idea that, in order for a child to develop leukemia, it is not enough that the child be exposed to leukemiogenic factor, but that it is necessary that the child be susceptible to the infirmity [22-24]. If we start with the premise, postulated by Greaves, that ALL is the result of two hits, one that occurred in the intrauterine stage or in a stage very early in life and another hit that was necessary afterward [25,26], then this would predict that each child that develops ALL must have had a prior susceptibility for developing the infirmity; otherwise, the children that are exposed to the "second hit", given that they do not have the first, will not be able

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

5

Consequently, an error that has been committed in many epidemiological studies is that these studies have been carried out without taking into account the susceptibility of the child for the infirmity [29]. Our group was the first to demonstrate that environmental fac‐ tors have an important weight in the development of ALL in children with a high suscepti‐ bility for the illness, such as those with Down syndrome (DS) [7,29]. By including children with DS, not only as cases but also as controls, it has been possible to improve the precision of the sampling size, because even with relatively small sample sizes, it was possible to

Susceptibility to ALL has been studied from two perspectives: one that deals with genes or syndromes that increase the risk of developing ALL; the other, with the genes or alterations

There are genetic rearrangements, such as MLL/AF4, the involvement of which in the devel‐ opment of ALL in children is indisputable [13]. In fact, Greaves postulated that the MLL/AF4 is a necessary and sufficient cause for the development of ALL in children, espe‐ cially in infants [13,26]. However, some researchers have demonstrated that this rearrange‐ ment may appear with an important frequency in older children and that even the twin of the children that develop ALL could lose the MLL/AF4 rearrangement in later years of life [31,32]. In a chapter of this book, it is shown how exposure during pregnancy to inhibitors of topoisomerase II is a risk factor for the offspring of the pregnancy to develop ALL with the presence of genetic rearrangements MLL. There are no studies that demonstrate that chil‐ dren that are born with genetic rearrangements in MLL, upon exposure to determined envi‐ ronmental factors, have a greater risk of developing ALL. Such studies are difficult to perform, because the frequency of genetic rearrangements in MLL in children without ALL

Among the syndromes that predispose to ALL are SD, ataxia, telangiectasia, and Fanconi anemia [24]. Although these children present an elevated risk for developing ALL, not all develop the disease [33]. It is possible that these children would have to be exposed to

identify a number of important environmental factors associated with ALL [7,30].

that increase the effect of the environmental exposure for a child to develop ALL.

is estimated to be less that 1 in 10000 live births [13].

to develop the disease [13,27,28].

**3. Susceptibility**

Nevertheless, the principal importance of the hypothesis of Greaves cannot be questioned, because it does not exclude what epidemiological methods have been able to demonstrate concerning late infection [12]. These data are conclusive in showing that, in the majority of cases, ALL originates during intrauterine life [13] and that proliferation of the B cells, in fact, the time in which the highest peak of proliferation occurs, is during the first year of life [12]. All these findings permit the deduction that ALL requires a first "hit" in the intrauterine stage and another hit during a later stage of life and that some infections may play a very important role in the causality of B-cell precursors of ALL.

#### **2. Exposure**

ALL has been associated with different environmental risk factors [14,15]; however, the only environmental factor that is universally accepted as being associated with ALL is exposure to X-rays *in utero*[14]. The identification of environmental factors has had various problems, one of which is the effect of the sample size on statistical power [15-18]. ALL is an infirmity with a very low frequency, which makes it difficult for studies to attain a sample size appro‐ priate for identifying an association with an environmental risk factor [16,17]. Another prob‐ lem is that most of the environmental factors that are associated with leukemia, such as exposure to X-rays or exposure to very low frequency magnetic fields, have a very low fre‐ quency of occurrence [16,19,20]. The study design that has been used the most to search for associations with ALL is the case-control study; this type of study has the limitation that it has low efficiency for identifying associations when the frequency of exposure is very low [16,17]. Another limitation in determining environmental exposure is that the greater part of the instruments used to evaluate such exposures either have not been validated for this pur‐ pose or are not sufficiently sensitive to detect the presence of such exposure, as is the case for exposure to infections during the first year of life [11] or for exposure to extremely low frequency magnetic fields [19].

Most experimental designs have the limitation that they cannot evaluate various independ‐ ent variables at the same time [21]. Multivariate analysis that is used to evaluate the effect of an independent variable, adjusted for the effect of various control variables or potential con‐ founders, implies a modeling with only one or two predictor variables for the disease [21]. ALL is potentially the result of the presence not of one or two independent variables, but of many risk factors that act at the same time to provoke the development of the illness [1]. Ac‐ cording to the multicausal theory, illnesses must have at least two risk factors that lead to the development of the illness; the majority of multivariate models, such as logistic regres‐ sion, do not permit this type of simultaneous evaluations.

One of the limitations in trying to identify the association between environmental factors and the development of ALL is that not taken into account is the idea that, in order for a child to develop leukemia, it is not enough that the child be exposed to leukemiogenic factor, but that it is necessary that the child be susceptible to the infirmity [22-24]. If we start with the premise, postulated by Greaves, that ALL is the result of two hits, one that occurred in the intrauterine stage or in a stage very early in life and another hit that was necessary afterward [25,26], then this would predict that each child that develops ALL must have had a prior susceptibility for developing the infirmity; otherwise, the children that are exposed to the "second hit", given that they do not have the first, will not be able to develop the disease [13,27,28].

Consequently, an error that has been committed in many epidemiological studies is that these studies have been carried out without taking into account the susceptibility of the child for the infirmity [29]. Our group was the first to demonstrate that environmental fac‐ tors have an important weight in the development of ALL in children with a high suscepti‐ bility for the illness, such as those with Down syndrome (DS) [7,29]. By including children with DS, not only as cases but also as controls, it has been possible to improve the precision of the sampling size, because even with relatively small sample sizes, it was possible to identify a number of important environmental factors associated with ALL [7,30].

## **3. Susceptibility**

age [9,10]. In addition, data are emerging from epidemiological databases that the idea of early infection being a protective factor for ALL originated due to a bias (non-differential misclassification) [11] and that, in reality, no such association exists. At any rate, determina‐ tion of whether a child suffered from different infections during the first year of life is ex‐ tremely difficult; for this reason, the empirical reference will need to be improved in order to

Nevertheless, the principal importance of the hypothesis of Greaves cannot be questioned, because it does not exclude what epidemiological methods have been able to demonstrate concerning late infection [12]. These data are conclusive in showing that, in the majority of cases, ALL originates during intrauterine life [13] and that proliferation of the B cells, in fact, the time in which the highest peak of proliferation occurs, is during the first year of life [12]. All these findings permit the deduction that ALL requires a first "hit" in the intrauterine stage and another hit during a later stage of life and that some infections may play a very

ALL has been associated with different environmental risk factors [14,15]; however, the only environmental factor that is universally accepted as being associated with ALL is exposure to X-rays *in utero*[14]. The identification of environmental factors has had various problems, one of which is the effect of the sample size on statistical power [15-18]. ALL is an infirmity with a very low frequency, which makes it difficult for studies to attain a sample size appro‐ priate for identifying an association with an environmental risk factor [16,17]. Another prob‐ lem is that most of the environmental factors that are associated with leukemia, such as exposure to X-rays or exposure to very low frequency magnetic fields, have a very low fre‐ quency of occurrence [16,19,20]. The study design that has been used the most to search for associations with ALL is the case-control study; this type of study has the limitation that it has low efficiency for identifying associations when the frequency of exposure is very low [16,17]. Another limitation in determining environmental exposure is that the greater part of the instruments used to evaluate such exposures either have not been validated for this pur‐ pose or are not sufficiently sensitive to detect the presence of such exposure, as is the case for exposure to infections during the first year of life [11] or for exposure to extremely low

Most experimental designs have the limitation that they cannot evaluate various independ‐ ent variables at the same time [21]. Multivariate analysis that is used to evaluate the effect of an independent variable, adjusted for the effect of various control variables or potential con‐ founders, implies a modeling with only one or two predictor variables for the disease [21]. ALL is potentially the result of the presence not of one or two independent variables, but of many risk factors that act at the same time to provoke the development of the illness [1]. Ac‐ cording to the multicausal theory, illnesses must have at least two risk factors that lead to the development of the illness; the majority of multivariate models, such as logistic regres‐

lend greater support to this hypothesis.

**2. Exposure**

frequency magnetic fields [19].

important role in the causality of B-cell precursors of ALL.

4 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

sion, do not permit this type of simultaneous evaluations.

Susceptibility to ALL has been studied from two perspectives: one that deals with genes or syndromes that increase the risk of developing ALL; the other, with the genes or alterations that increase the effect of the environmental exposure for a child to develop ALL.

There are genetic rearrangements, such as MLL/AF4, the involvement of which in the devel‐ opment of ALL in children is indisputable [13]. In fact, Greaves postulated that the MLL/AF4 is a necessary and sufficient cause for the development of ALL in children, espe‐ cially in infants [13,26]. However, some researchers have demonstrated that this rearrange‐ ment may appear with an important frequency in older children and that even the twin of the children that develop ALL could lose the MLL/AF4 rearrangement in later years of life [31,32]. In a chapter of this book, it is shown how exposure during pregnancy to inhibitors of topoisomerase II is a risk factor for the offspring of the pregnancy to develop ALL with the presence of genetic rearrangements MLL. There are no studies that demonstrate that chil‐ dren that are born with genetic rearrangements in MLL, upon exposure to determined envi‐ ronmental factors, have a greater risk of developing ALL. Such studies are difficult to perform, because the frequency of genetic rearrangements in MLL in children without ALL is estimated to be less that 1 in 10000 live births [13].

Among the syndromes that predispose to ALL are SD, ataxia, telangiectasia, and Fanconi anemia [24]. Although these children present an elevated risk for developing ALL, not all develop the disease [33]. It is possible that these children would have to be exposed to some environmental factor in order to develop ALL, as has been demonstrated for chil‐ dren with SD [4,15,29,33,34].

years of age [25], for development of ALL. Exposure of a child to radiation (x ray for exam‐ ple) in the earlier stages of life has been associated with a greater risk of ALL [45] and, in addition, the leukemia has a shorter latency period. Hertz-Picciotto et al. underscored the importance of evaluating the time of life or stage of development of the tissues at which the exposure occurs [46], because for two individuals who may have been exposed to the same factor, the effect of said exposure will vary according to the stage of development of the in‐ dividual or of the particular organ [47-52]. Some of the factors that can influence the toxicity of a substance in an organism may vary according to the individual's age. Such is the case for the absorption, metabolism, detoxification, and excretion of xenobiotic compounds. Simi‐ larly, for children, there can exist an immaturity in the biochemical and physiological func‐ tions of the majority of the systems of the body, as well as variation in the bodily composition (content of water, fat, protein, and minerals) [48,52-54]. These factors may make

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

7

Considering the importance of the time at which the exposure occurs separately from the stage of development of the organism that may be affected, it is important to evaluate whether the exposure occurred in the prenatal stage, during the pregnancy, or in the postnatal period [28,50]. For example, exposures that affect a maternal ovum may have occurred peri-conceptionally or even a long time before conception, given that the ova are present, al‐ ready formed, in the woman [47]. Among the exposures that affect the sperm or the substan‐ ces that can concentrate in the semen, said exposures can only cause damage periconceptionally, because sperm and seminal fluid involved in the fertilization were formed hours, or a few days, prior to the conception [47]. It has also been observed that some sub‐ stances that are stored in the fat or in the bones of the mother may be removed during the pregnancy and cause injury to the fetus [47]. Some significant exposure during pregnancy may be more related to the presence of the rearrangement MLL/AF4 [13,56], because the cas‐ es of leukemia that occur in infants generally belong to this type of leukemia, whereas expo‐ sures that occur at 2–4 years of age may be more related to the B-cell precursor ALL with

the neonate, for example, very sensitive to chemical substances [52,53,55].

ETV6/RUNX1, because this is the peak age of onset for this disease [13,43,57].

Infections may have another action: an increase in the proliferation of B cells may increase the risk that the cells being exposed to leukemiogenic agent would lead to ALL [7,12].

On the other hand, it is not only necessary that the cells have proliferated, but also it is nec‐ essary that, in that moment, there be a niche in the bone marrow which would permit the growth and the expansion of that leukemia clone [28]. In a book in the series In Tech, Pelayo has described the function of the microenvironment of the bone marrow in the development of ALL [58,59]. Today, it is known that the alterations not only must occur in the cancerous cells, what confers upon them the capacity for mutations and genomic instability, that changes the cycles of cell regulation and energy consumption, evades or destroys the im‐ mune system and generates mechanisms of inflammation that lead to tumor propagation [60]. In addition to all this, cancerous cells are capable of causing changes in their microen‐ vironment to generate an environment in which a cancerous cell can form a "nest", a micro‐ environment that generates tumor invasion, and a microenvironment that favors the

There also exists susceptibility determined by polymorphisms that increase the effect of lue‐ kemiogenic factors, through which children develop ALL. Examples are those related to the polymorphisms of methyl-n-transferase and cytochrome p-450. Some polymorphisms of these genes have been associated to a greater toxic effect for benzene and other factors that are potentially leukemiogenic [35-39].

Some nutritional alterations also have been seen to increase the effect of some potentially leukemiogenic factors, a possible examples is reduction in the consumption of vitamin A, as it is known that vitamin A reduces the effect of exposure to carcinogens in tobacco smoke [40]. Tobacco smoke contains substances, such as benzene, which are known to have a leu‐ kemiogenic effect [41,42].

## **4. Vulnerable period**

The frequency of ALL has a characteristic peak at 2–5 years of age [23,24]. In the Mexi‐ can population, there appears another age peak at 6–9 years of age [43]. This peak pri‐ marily results from B-cell precursor ALL and that has the genetic rearrangement ETV6/ RUNX1 [13,23].

In an attempt to explain the cause of this peak, a series of hypotheses have been generated [23], among which that proposed by Greaves stands out. Greaves commented that this age peak reflects the start of a greater immunological response and, in particular, it is in direct relation to the capacity to produce immunoglobulins [12]. Greaves assumes that, after the first year of life, the possibility is increased that a previously mutated cell may undergo a second mutation and this brings with it the development of ALL [12].

In the case of ALL, it has been established that, for children who are born with a greater sus‐ ceptibility to ALL, such as those children born with the genetic rearrangement that involves MLL, the age at onset of ALL is earlier, generally during the first year of life. It is estimated that those children have a 100% probability of developing ALL [13]. In contrast, children who are born with the genetic rearrangement ETV6/RUNX1 have a 25% probability of de‐ veloping ALL and their peak age at onset (2–5 years of age) is later than that for the children born with the genetic rearrangement that involves MLL [13]. This leads one to think that the peak age of onset of ALL reflects the degree of susceptibility with which a child is born and, on the other hand, the degree of proliferation of the cells involved in the development of the disease [1,43]. A similar situation exists for retinoblastoma, in which the age at onset of ALL reflects the degree of proliferation of the cells in the retina and for osteosarcoma which ap‐ pears earlier in females than in males, starting at the growth spurt in adolescence [1,28,44].

Another aspect that, despite its great importance in epidemiological research, is on occa‐ sions overlooked is the stage of life at which the exposure to a carcinogenic agent occurs. Greaves has pointed out the importance of the infection occurring at a particular period, 2–3 years of age [25], for development of ALL. Exposure of a child to radiation (x ray for exam‐ ple) in the earlier stages of life has been associated with a greater risk of ALL [45] and, in addition, the leukemia has a shorter latency period. Hertz-Picciotto et al. underscored the importance of evaluating the time of life or stage of development of the tissues at which the exposure occurs [46], because for two individuals who may have been exposed to the same factor, the effect of said exposure will vary according to the stage of development of the in‐ dividual or of the particular organ [47-52]. Some of the factors that can influence the toxicity of a substance in an organism may vary according to the individual's age. Such is the case for the absorption, metabolism, detoxification, and excretion of xenobiotic compounds. Simi‐ larly, for children, there can exist an immaturity in the biochemical and physiological func‐ tions of the majority of the systems of the body, as well as variation in the bodily composition (content of water, fat, protein, and minerals) [48,52-54]. These factors may make the neonate, for example, very sensitive to chemical substances [52,53,55].

some environmental factor in order to develop ALL, as has been demonstrated for chil‐

6 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

There also exists susceptibility determined by polymorphisms that increase the effect of lue‐ kemiogenic factors, through which children develop ALL. Examples are those related to the polymorphisms of methyl-n-transferase and cytochrome p-450. Some polymorphisms of these genes have been associated to a greater toxic effect for benzene and other factors that

Some nutritional alterations also have been seen to increase the effect of some potentially leukemiogenic factors, a possible examples is reduction in the consumption of vitamin A, as it is known that vitamin A reduces the effect of exposure to carcinogens in tobacco smoke [40]. Tobacco smoke contains substances, such as benzene, which are known to have a leu‐

The frequency of ALL has a characteristic peak at 2–5 years of age [23,24]. In the Mexi‐ can population, there appears another age peak at 6–9 years of age [43]. This peak pri‐ marily results from B-cell precursor ALL and that has the genetic rearrangement ETV6/

In an attempt to explain the cause of this peak, a series of hypotheses have been generated [23], among which that proposed by Greaves stands out. Greaves commented that this age peak reflects the start of a greater immunological response and, in particular, it is in direct relation to the capacity to produce immunoglobulins [12]. Greaves assumes that, after the first year of life, the possibility is increased that a previously mutated cell may undergo a

In the case of ALL, it has been established that, for children who are born with a greater sus‐ ceptibility to ALL, such as those children born with the genetic rearrangement that involves MLL, the age at onset of ALL is earlier, generally during the first year of life. It is estimated that those children have a 100% probability of developing ALL [13]. In contrast, children who are born with the genetic rearrangement ETV6/RUNX1 have a 25% probability of de‐ veloping ALL and their peak age at onset (2–5 years of age) is later than that for the children born with the genetic rearrangement that involves MLL [13]. This leads one to think that the peak age of onset of ALL reflects the degree of susceptibility with which a child is born and, on the other hand, the degree of proliferation of the cells involved in the development of the disease [1,43]. A similar situation exists for retinoblastoma, in which the age at onset of ALL reflects the degree of proliferation of the cells in the retina and for osteosarcoma which ap‐ pears earlier in females than in males, starting at the growth spurt in adolescence [1,28,44]. Another aspect that, despite its great importance in epidemiological research, is on occa‐ sions overlooked is the stage of life at which the exposure to a carcinogenic agent occurs. Greaves has pointed out the importance of the infection occurring at a particular period, 2–3

second mutation and this brings with it the development of ALL [12].

dren with SD [4,15,29,33,34].

kemiogenic effect [41,42].

**4. Vulnerable period**

RUNX1 [13,23].

are potentially leukemiogenic [35-39].

Considering the importance of the time at which the exposure occurs separately from the stage of development of the organism that may be affected, it is important to evaluate whether the exposure occurred in the prenatal stage, during the pregnancy, or in the postnatal period [28,50]. For example, exposures that affect a maternal ovum may have occurred peri-conceptionally or even a long time before conception, given that the ova are present, al‐ ready formed, in the woman [47]. Among the exposures that affect the sperm or the substan‐ ces that can concentrate in the semen, said exposures can only cause damage periconceptionally, because sperm and seminal fluid involved in the fertilization were formed hours, or a few days, prior to the conception [47]. It has also been observed that some sub‐ stances that are stored in the fat or in the bones of the mother may be removed during the pregnancy and cause injury to the fetus [47]. Some significant exposure during pregnancy may be more related to the presence of the rearrangement MLL/AF4 [13,56], because the cas‐ es of leukemia that occur in infants generally belong to this type of leukemia, whereas expo‐ sures that occur at 2–4 years of age may be more related to the B-cell precursor ALL with ETV6/RUNX1, because this is the peak age of onset for this disease [13,43,57].

Infections may have another action: an increase in the proliferation of B cells may increase the risk that the cells being exposed to leukemiogenic agent would lead to ALL [7,12].

On the other hand, it is not only necessary that the cells have proliferated, but also it is nec‐ essary that, in that moment, there be a niche in the bone marrow which would permit the growth and the expansion of that leukemia clone [28]. In a book in the series In Tech, Pelayo has described the function of the microenvironment of the bone marrow in the development of ALL [58,59]. Today, it is known that the alterations not only must occur in the cancerous cells, what confers upon them the capacity for mutations and genomic instability, that changes the cycles of cell regulation and energy consumption, evades or destroys the im‐ mune system and generates mechanisms of inflammation that lead to tumor propagation [60]. In addition to all this, cancerous cells are capable of causing changes in their microen‐ vironment to generate an environment in which a cancerous cell can form a "nest", a micro‐ environment that generates tumor invasion, and a microenvironment that favors the development of metastasis [58-61]. Such changes in the cells make them even more vulnera‐ ble to exposure to carcinogenic substances [62-64].

the "sufficent cause completed" the diseases was not developed. An argument that could emerge is that, as the sufficient cause was not reality completed, it is for this reason that the individual did not develop the disease. At this point, we are left without possibilities of demonstrating that said hypothesis may be falsifiable. In one sense, the illness itself is the sufficient cause and therefore stops being two separate variables and no longer fulfills its function of prediction, given that one cannot say that an individual completed the sufficient cause and consequently goes on to develop the disease; we know that the sufficient cause

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

9

**Figure 1.** Interaction between a gradient of susceptibility to a disease and a gradient of exposure to environmental risk factors. To develop ALL, an individual with a higher susceptibility, as determined by the interplay of genetic fac‐ tors, would need only a lower exposure, as determined by the unknown, possibly synergistic, interplay of the charac‐ teristics of the exposure. Conversely, the higher the exposure, the lower the susceptibility that would be needed to

The hypothesis that is set forth here is bounded by three phenomena, the "exposure", the "susceptibility", and the "vulnerable period" (Fig. 2). This model includes only these three component causes that are necessary for a child to develop the illness. As was described in the initial part of this chapter, these three phenomena are interrelated and there exists a gra‐ dient which indicates that, when there is an excess of one of these components, less is need‐

ed of the other two components in order to develop the illness (Fig. 1).

has been completed only when the individual becomes ill.

result in development of the disease.

## **5. Down syndrome model: Advantage of a design with cases and controls selected for susceptibility**

Robinson was one of the first to propose that if a child with DS is studied, identification of the effect of the major portion of environmental factors in the development of ALL in chil‐ dren could be achieved [33]. Children with DS have a higher risk for developing leukemias, not only myeloid leukemias, but also lymphoblastic leukemias. In the lymphoblastic leuke‐ mias, the participation of the genes, *JAK 1* and *JAK2*, have a definite affect in these children developing the disease [65].

The study of children with a high susceptibility to ALL has permitted, even with a smaller sample size, the identification of the role that some environmental factors play in the devel‐ opment of ALL. The risks (odds ratios) encountered when comparing the population of chil‐ dren with ALL with DS and a population of healthy children with DS have been relatively higher than those reported when comparing healthy children without high susceptibility to the disease as controls. We have called this approach "studies of cases and controls selected by susceptibility". The advantages that we have reported about this design is that it im‐ proves the sampling power and the precision of the estimators [66].

## **6. Theory as a model of prediction**

Theories are considered as a tool or instrument that can be used to predict [67].

The epidemiological theory that attempts to predict the origin of diseases in human popula‐ tions is the Sufficient-Component Cause model [68]. This theory underscores the idea that diseases are multicausal and that it is necessary that at least two component causes must be present or have occurred for an individual to develop said disease. Upon completing the component causes of the disease, then a sufficient cause has been completed and, in such case, the person will develop the disease [68].

The criteria of demarcation to determine if a hypothesis is scientific or not are that the refu‐ tationism proposes that the hypothesis be deducible, that there exists a way to test the hy‐ pothesis empirically, and that the hypothesis be be falsifiable [67,68].

With respect to the multicausal theory and the Sufficient-Component Causes model, the em‐ pirical referent that the sufficient cause has been completed is only the disease itself; its ori‐ gin is deducible because this theory assumes that all illnesses arises from the action of at least two component causes. However, there is no manner in which this hypothesis can be falsified, because whatever model proposed to show that the sufficient cause has been com‐ pleted at the time of the attempt at falsification and consequently to demostrate that with the "sufficent cause completed" the diseases was not developed. An argument that could emerge is that, as the sufficient cause was not reality completed, it is for this reason that the individual did not develop the disease. At this point, we are left without possibilities of demonstrating that said hypothesis may be falsifiable. In one sense, the illness itself is the sufficient cause and therefore stops being two separate variables and no longer fulfills its function of prediction, given that one cannot say that an individual completed the sufficient cause and consequently goes on to develop the disease; we know that the sufficient cause has been completed only when the individual becomes ill.

development of metastasis [58-61]. Such changes in the cells make them even more vulnera‐

**5. Down syndrome model: Advantage of a design with cases and controls**

Robinson was one of the first to propose that if a child with DS is studied, identification of the effect of the major portion of environmental factors in the development of ALL in chil‐ dren could be achieved [33]. Children with DS have a higher risk for developing leukemias, not only myeloid leukemias, but also lymphoblastic leukemias. In the lymphoblastic leuke‐ mias, the participation of the genes, *JAK 1* and *JAK2*, have a definite affect in these children

The study of children with a high susceptibility to ALL has permitted, even with a smaller sample size, the identification of the role that some environmental factors play in the devel‐ opment of ALL. The risks (odds ratios) encountered when comparing the population of chil‐ dren with ALL with DS and a population of healthy children with DS have been relatively higher than those reported when comparing healthy children without high susceptibility to the disease as controls. We have called this approach "studies of cases and controls selected by susceptibility". The advantages that we have reported about this design is that it im‐

proves the sampling power and the precision of the estimators [66].

pothesis empirically, and that the hypothesis be be falsifiable [67,68].

Theories are considered as a tool or instrument that can be used to predict [67].

The epidemiological theory that attempts to predict the origin of diseases in human popula‐ tions is the Sufficient-Component Cause model [68]. This theory underscores the idea that diseases are multicausal and that it is necessary that at least two component causes must be present or have occurred for an individual to develop said disease. Upon completing the component causes of the disease, then a sufficient cause has been completed and, in such

The criteria of demarcation to determine if a hypothesis is scientific or not are that the refu‐ tationism proposes that the hypothesis be deducible, that there exists a way to test the hy‐

With respect to the multicausal theory and the Sufficient-Component Causes model, the em‐ pirical referent that the sufficient cause has been completed is only the disease itself; its ori‐ gin is deducible because this theory assumes that all illnesses arises from the action of at least two component causes. However, there is no manner in which this hypothesis can be falsified, because whatever model proposed to show that the sufficient cause has been com‐ pleted at the time of the attempt at falsification and consequently to demostrate that with

**6. Theory as a model of prediction**

case, the person will develop the disease [68].

ble to exposure to carcinogenic substances [62-64].

8 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**selected for susceptibility**

developing the disease [65].

**Figure 1.** Interaction between a gradient of susceptibility to a disease and a gradient of exposure to environmental risk factors. To develop ALL, an individual with a higher susceptibility, as determined by the interplay of genetic fac‐ tors, would need only a lower exposure, as determined by the unknown, possibly synergistic, interplay of the charac‐ teristics of the exposure. Conversely, the higher the exposure, the lower the susceptibility that would be needed to result in development of the disease.

The hypothesis that is set forth here is bounded by three phenomena, the "exposure", the "susceptibility", and the "vulnerable period" (Fig. 2). This model includes only these three component causes that are necessary for a child to develop the illness. As was described in the initial part of this chapter, these three phenomena are interrelated and there exists a gra‐ dient which indicates that, when there is an excess of one of these components, less is need‐ ed of the other two components in order to develop the illness (Fig. 1).

tremely low frequency [69], etc. The approach of the precautionary principle should be fol‐ lowed, in that although the causal evidence is not absolute, the risk or the effect of the illness is so serious that putting oneself in contact the risk factor should be avoided [66,70]. Similar‐ ly, for children of parents who underwent elevated exposure to leukemiogenic factors dur‐ ing the pregnancy, it may happen that, although these children may have been born "normal", it is possible that they had been born with a high susceptibility to the ALL, which

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

11

Susceptibility to ALL is a constitutive condition or one that is acquired in an early stage of life. Exposure to a leukemiogenic agent will have an affect to the extent of the intensity of the exposure and the degree of susceptibility to the disease or the intrinsic factors that modi‐ fy the form in which the child's bodily tissues respond to this exposure. However, this must occur at a specific moment when a cell is proliferating and where the conditions around the cell are appropriate for the cell to be converted into a leukemic clone and finally develops

As the absolute truth described in the Bible says, "There is a time for everything…" [71]

This chapter contains results of studies that were funded by grants from the National Coun‐ cil of Science and Technology (CONACYT, Mexico; CB-2007-83949; 2007-C01-71223; and 2010-1-141026) and from the Mexican Institute of Social Security (IMSS, Mexico; FIS/ PROT/56 and FIS/IMSS/PROT/G10/846). Translation of the original Spanish into English was financed by CONACYT and the Coordination of Research in Health through the Division of Development and Research. The author thanks Dr. Arturo Fajardo-Gutiérrez (Unit of Clini‐ cal Epidemiology, IMSS, Mexico) whose comments enriched the hypothesis presented here

Coordination of Research in Health, Mexican Institute of Social Security, Mexico City, Mexico

[1] Mejía-Aranguré JM, Pérez-Saldivar ML, Pelayo-Camacho R, Fuentes-Pananá E, Bek‐ ker-Mendez C, Morales-Sánchez A, Duarte-Rodríguez DA, Fajardo-Gutiérrez A.

is not possible to identify simply by observation.

and Veronica Yakoleff for translating the text.

Address all correspondence to: juan.mejiaa@imss.gob.mx

the disease.

**Acknowledgments**

**Author details**

**References**

Juan Manuel Mejía-Aranguré

**Figure 2.** Interaction among the three phenomena. Acute lymphoblastic leukemia (AL) in childhood is the result of the interactions among three phenomena: the gradient of susceptibility, the gradient of exposure to carcinogenic en‐ vironmental factors, and the tissue vulnerability period.

## **7. Conclusions**

Current models to identify the environmental causes of ALL have limitations that could lead to years of studies and the investment enormous sums of money, yet still continue without successfully determining the factors associated with ALL.

This proposed model of susceptibility, exposure, and vulnerable period permits boundaries to be drawn around the factors that could potentially influence the development of the dis‐ ease and, in addition, permits the development of new methods for the study of the environ‐ mental causes of ALL in children, such as the study of cases and controls selected by susceptibility.

Children that are born with a high susceptibility to ALL, such as children with SD, should be the first among those that should be protected from exposure to environmental factors that potentially provoke ALL, such as tobacco smoke [29], exposure to magnetic fields of ex‐ tremely low frequency [69], etc. The approach of the precautionary principle should be fol‐ lowed, in that although the causal evidence is not absolute, the risk or the effect of the illness is so serious that putting oneself in contact the risk factor should be avoided [66,70]. Similar‐ ly, for children of parents who underwent elevated exposure to leukemiogenic factors dur‐ ing the pregnancy, it may happen that, although these children may have been born "normal", it is possible that they had been born with a high susceptibility to the ALL, which is not possible to identify simply by observation.

Susceptibility to ALL is a constitutive condition or one that is acquired in an early stage of life. Exposure to a leukemiogenic agent will have an affect to the extent of the intensity of the exposure and the degree of susceptibility to the disease or the intrinsic factors that modi‐ fy the form in which the child's bodily tissues respond to this exposure. However, this must occur at a specific moment when a cell is proliferating and where the conditions around the cell are appropriate for the cell to be converted into a leukemic clone and finally develops the disease.

As the absolute truth described in the Bible says, "There is a time for everything…" [71]

## **Acknowledgments**

This chapter contains results of studies that were funded by grants from the National Coun‐ cil of Science and Technology (CONACYT, Mexico; CB-2007-83949; 2007-C01-71223; and 2010-1-141026) and from the Mexican Institute of Social Security (IMSS, Mexico; FIS/ PROT/56 and FIS/IMSS/PROT/G10/846). Translation of the original Spanish into English was financed by CONACYT and the Coordination of Research in Health through the Division of Development and Research. The author thanks Dr. Arturo Fajardo-Gutiérrez (Unit of Clini‐ cal Epidemiology, IMSS, Mexico) whose comments enriched the hypothesis presented here and Veronica Yakoleff for translating the text.

## **Author details**

**Figure 2.** Interaction among the three phenomena. Acute lymphoblastic leukemia (AL) in childhood is the result of the interactions among three phenomena: the gradient of susceptibility, the gradient of exposure to carcinogenic en‐

Current models to identify the environmental causes of ALL have limitations that could lead to years of studies and the investment enormous sums of money, yet still continue without

This proposed model of susceptibility, exposure, and vulnerable period permits boundaries to be drawn around the factors that could potentially influence the development of the dis‐ ease and, in addition, permits the development of new methods for the study of the environ‐ mental causes of ALL in children, such as the study of cases and controls selected by

Children that are born with a high susceptibility to ALL, such as children with SD, should be the first among those that should be protected from exposure to environmental factors that potentially provoke ALL, such as tobacco smoke [29], exposure to magnetic fields of ex‐

vironmental factors, and the tissue vulnerability period.

successfully determining the factors associated with ALL.

10 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**7. Conclusions**

susceptibility.

Juan Manuel Mejía-Aranguré

Address all correspondence to: juan.mejiaa@imss.gob.mx

Coordination of Research in Health, Mexican Institute of Social Security, Mexico City, Mexico

## **References**

[1] Mejía-Aranguré JM, Pérez-Saldivar ML, Pelayo-Camacho R, Fuentes-Pananá E, Bek‐ ker-Mendez C, Morales-Sánchez A, Duarte-Rodríguez DA, Fajardo-Gutiérrez A. Childhood Acute Leukemias in Hispanic Population: Differences by Age Peak and Immunophenotype. In: Faderl S. (ed.) Novel aspects in acute lymphoblastic leuke‐ mia. Rijeka: In Tech; 2011. P3-32.

[11] Roman E, Simpson J, Ansell P, Lightfoot T, Smith A. Infectious proxies and child‐ hood leukaemia: findings from the United Kingdom Childhood Cancer Study

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

13

[12] Greaves M. Infection, immune responses and the aetiology of childhood leukaemia.

[13] Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukae‐

[14] Mejía-Aranguré JM, Ortega-Alvarez MC, Fajardo-Gutiérrez A. Epidemiología de las leucemias agudas en niños (Parte I). Revistamédica del InstitutoMexicano del Seguro

[15] Mejía-Aranguré JM, Ortega-Alvarez MC, Fajardo-Gutiérrez A. Epidemiología de las leucemias agudas en niños (Parte II). RevistamédicadelInstitutoMexicano del Seguro

[16] Gufferman S. Methodologic approaches to studying environmental factors in child‐ hood cancer. Environmental health perspectives 1998; 106:(Suppl 3):881-6.

[17] Linet MS, Wacholder S, Zahm SH. Interpreting epidemiologic research: lessons from

[18] Woodruff TJ, Axelrad DA, Kyle AD, Nweke O, Miller GG, Hurley BJ. Trends in Envi‐ ronmentally related childhood illnesses. Pediatrics 2004; 113(4 Suppl):1133-40.

[19] Greenland S, Kheifets L. Leukemia attributable to residential magnetic fields: Results from analyses allowing for study biases. Risk analysis: an official publication of the

[20] Kheifets L, Afifi AA, Shimkhada R. Public health impact of extremely low-frequency electromagnetic fields. Environmental health perspectives 2006; 114(10):1532-7.

[21] Kleinbaum DG, Klein M. Important special cases of the logistic model. In Logistic Re‐

[22] Stewart A. Aetiology of childhood malignancies. British medical journal 1961:1(5224):

[24] Eden T. Aetiology of childhood leukaemia. Cancer treatment reviews 2010; 36(4):

[25] Greaves M. Molecular genetics, natural history and the demise of childhood leukae‐

[26] Greaves M. Biology of leukemia: An overview. In: Henderson ES, Lister TA, Greaves

[23] Greaves MF. Aetiology of acute leukaemia. Lancet 1997; 349(9048):344-9.

studies of childhood cancer. Pediatrics 2003; 112(1 Pt 2):218-32.

(UKCCS).Blood cells, molecules & diseases2009; 42(2):126-8.

Nature reviews. Cancer 2006; 6(3): 193-203.

mia. Nature reviews. Cancer 2003;3(9):639-49.

Society for Risk Analysis 2006; 26(2):471-82.

gression. Springer Science: New York 2010: 41-71.

mia. European journal of cancer 1999; 35(14):1941-53.

MF. Leukemia. 7hd ed. Philadelphia:Saunders 2002:8-18.

Social 2005; 43(4):323-33

Social 2005; 43(5):401-9.

452-60.

286-97.


[11] Roman E, Simpson J, Ansell P, Lightfoot T, Smith A. Infectious proxies and child‐ hood leukaemia: findings from the United Kingdom Childhood Cancer Study (UKCCS).Blood cells, molecules & diseases2009; 42(2):126-8.

Childhood Acute Leukemias in Hispanic Population: Differences by Age Peak and Immunophenotype. In: Faderl S. (ed.) Novel aspects in acute lymphoblastic leuke‐

[2] Mejía-Aranguré JM, Bonilla M, Lorenzana R, Juárez-Ocaña S, de Reyes G, Pérez-Sal‐ divar ML, Guadalupe González-Miranda, Roberto Bernáldez-Ríos, Antonio Ortiz-Fernández, Manuel Ortega-Alvarez, María del Carmen Martínez-García, Arturo Fajardo-Gutiérrez. Incidence of leukemias in children from El Salvador and Mexico

[3] Pérez-Saldivar ML, Fajardo-Gutiérrez A, Bernáldez-Ríos R, Martínez-Avalos A, Med‐ ina-Sanson A, Espinosa-Hernández L, Flores-Chapa JD, Amador-Sánchez R, Peñalo‐ za-González JG, Álvarez-Rodríguez FJ, Bolea-Murga V, Flores-Lujano J, Rodríguez-Zepeda MC, Rivera-Luna R, Dorantes-Acosta EM, Jiménez-Hernández E, Alvarado-Ibarra M, Velázquez-Aviña MM, Torres-Nava JR, Duarte-Rodríguez DA, Paredes-Aguilera R, Campo-Martínez MA, Cárdenas-Cardos R, Alamilla-Galicia PH, Bekker-Méndez VC, Ortega-Alvarez MC, Mejia-Arangure JM. Childhood acute leukemias are very frequent in Mexican population: descriptive epidemiology from all bor‐

[4] Taylor GM. Immunogenetics and the aetiology of childhood leukemia. Archives of

[5] Schmiegelow K, Vestergaard T, Nielsen SM, Hjalgrim H. Etiology of common child‐ hood acute lymphoblastic leukemia: the adrenal hypothesis. Leukemia 2008; 22(12):

[6] Azevedo-Silva F, Camargo B, Pombo-de-Oliveira MS. Implications of infectious dis‐ eases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic

[8] Richardson RB. Promotional etiology for common childhood acute lymphoblastic leukemia: The infective lymphoid recovery hypothesis. Leukemia research 2011;

[9] Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, McKinney PA, Birch JM, Greaves M, Eden T. United Kingdom Childhood Cancer Study Investigators. Child‐ hood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol2007; 165: 496–

[10] Rosenbaum PF, Buck GM, Brecher ML. Early child-care and preschool experience and the risk of childhood acute lymphoblastic leukemia. American journal of epi‐

leukemia. Brazilian journal of medical and biological research2010; 43(3):226-9 [7] Mejia-Arangure JM, Perez-Saldivar ML, Flores-Lujano J, Bekker-Mendez C, Pinto-Cardoso S, Duarte-RodíguezDA, Fajardo-Gutierrez A. Infections and acute leukemia in children with Down Syndrome. In: Dey S (ed.) Prenatal diagnosis and screening

City between 1996 and 2000: Population-based data. BMC Cancer 2005; 5:33

mia. Rijeka: In Tech; 2011. P3-32.

12 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

oughs of Mexico City. BMC Cancer 2011; 11:355.

for Down Syndrome. Rijeka: In Tech; 2011. p79-106.

disease in childhood1994; 70(2):77-81.

2137-41

35(11):1425-31.

demiology 2000; 152(5):1136-44.

504.


[27] Dickinson HO. The causes of childhood leukaemia. British medical journal 2005; 330(7503):1279-80.

[37] Infante-Rivard C, Krajinovic M, Labuda D, Sinnett D. Childhood acute lymphoblastic leukemia associated with parental alcohol consumption and polymorphisms of carci‐

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

15

[38] Krajinovic M, Sinnett H, Richer C, Labuda D, Sinnett D. Role of NQO1, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblas‐

[39] Gast A, Bermejo JL, Stanulla M, Burwinkel B, Schrappe M, Bartram CR, Hemminki K, Kumar R. Folate metabolic gene polymorphisms and childhood acute lymphoblas‐

[40] Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. Genetic polymor‐ phism of CYP genes, alone or in combination, as a risk modifier of tobacco-related

[41] InfanteRivard C, Krajinovic M, Labuda D, Sinnett D. Parental smoking, CYP1A1 ge‐ netic polymorphisms and childhood leukemia (Quebec, Canada). Cancer causes &

[42] Pyatt D, Hays S. A review of the potential association between childhood leukemia

[43] Bernaldez-Rios R, Ortega-Alvarez M, Perez-Saldivar ML,Alatoma-Medina NE, Del Campo-Martinez MA, Rodriguez-Zepeda MC, Montero-Ponce I, Franco-Ornelas S, Fernandez-Castillo G, Nuñez-Villegas N, Taboada-Flores MA, Flores-Lujano J, Ar‐ güelles-Sanchez ME, Juarez-Ocaña S, Fajardo-Gutierrez A, Mejia-Arangure JM. The age incidence of childhood B-cell precursor acute lymphoblastic leukemia in Mexico

[44] Mejía-Aranguré JM, Flores-Aguilar H, Juárez-Muñoz I, Vázquez-Langle J, Games-Eternod J, Pérez-Saldivar ML, Ortega-Alvarez MC, Rendón-Macías ME, Fajardo-Gu‐ tiérrez A. Edad de aparición de los diferentestumoresmalignos en la infancia.

[45] Miller RW. Special Susceptibility of the child to certain radiation-induced cancers.

[46] Hertz-Picciotto I, Pastore LM, Beaumont JJ. Timing and patterns of exposures during pregnancy and their implications for study methods. American journal of epidemiol‐

[47] Bearer CF. How are children different from adults? Environmental health perspec‐

[48] Losan AF, Anderson L, Roman E, Fear N, Wolf M, Whyatt R y cols. Workshop to identify critical windows of exposure for children's health: cancer work group sum‐

mary. Environmental health perspectives 2000; 108(Suppl 3):595-597.

cancers. Cancer epidemiology, biomarkers & prevention 2000; 9(1):3-28.

and benzene. Chemico-biological interactions 2010; 184(1-2):151-64

City. Journal of pediatric hematology/oncology 2008; 30 (3):199-203.

RevistaMédica delInstitutoMexicano delSeguro Social 2005;43 (1):25-37.

Environmental health perspectives 1995; 103(Suppl 6):41-44.

nogen-metabolizing genes. Epidemiology 2002; 13(3):277-81.

tic leukemia. International journal of cancer 2002; 97(2):230-6.

tic leukemia: a case-control study. Leukemia 2007; 21(2):320-5.

control 2000; 11(6):547-53.

ogy1996; 143:597-607.

tives 1995; 103(Suppl 6):7-12.


[37] Infante-Rivard C, Krajinovic M, Labuda D, Sinnett D. Childhood acute lymphoblastic leukemia associated with parental alcohol consumption and polymorphisms of carci‐ nogen-metabolizing genes. Epidemiology 2002; 13(3):277-81.

[27] Dickinson HO. The causes of childhood leukaemia. British medical journal 2005;

[28] Huntly BJP, Gilliland G. Leukemia stem cells and the evolution of cancer-stem-cell

[29] Mejía-Aranguré JM, Fajardo-Gutiérrez A, Flores-Aguilar H, Martínez-García MC, Salamanca-Gómez F, Palma-Padilla V, Paredes-Aguilera R, Bernáldez-Ríos R, Ortiz-Fernández A, Martínez-Avalos A, Gorodezky C. Environmental factors contributing to the development of childhood leukemia in children with Down's syndrome. Leu‐

[30] Flores-Lujano, Perez-SaldivarML , Fuentes-PananaEM, GorodezkyC, Bernaldez-RiosR, Del Campo-MartinezMA, Martinez-AvalosA, Medina-Sanson A, Paredes-AguileraR, Flores-ChapaJ De Diego, Bolea-MurgaV, Rodriguez-ZepedaMC, Rivera-LunaR, Palomo-ColliMA, Romero-GuzmanL , Perez-VeraP , Alvarado-IbarraM, Salamanca-GómezF, Fajardo-Gutierrez A,Mejía-AranguréJM. Breastfeeding and ear‐ ly infection in the aetiology of childhood leukaemia in Down syndrome. British jour‐

[31] Alondra Daniel-Cravioto, Cesar R. Gonzalez-Bonilla, Juan Manuel Mejia-Arangure, Maria Luisa Perez-Saldivar, Arturo Fajardo-Gutierrez, Elva Jimenez-Hernandez, Mi‐ lagros Hernandez-Serrano, Vilma Carolina Bekker-Mendez. Genetic rearrangement MLL/AF4 is most frequent in children with acute lymphoblastic leukemias in Mexico

[32] Chuk MK, McIntyre E, Small D, Brown P. Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clear‐

[33] Ross JA, Spector LG, Robison LL, Olshan AF. Epidemiology of leukemia in children

[34] Canfield KN, Spector LG, Robison LL, Lazovich D, Roesler M, Olshan AF, Smith FO, Heerema NA, Barnard DR, Blair CK, Ross JA. Childhood and maternal infections and risk of acute leukemia in children with Down syndrome: a report from the Chil‐

[35] Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1

[36] Krajinovic M, Richer C, Sinnet H, Labuda D, Sinnett D. Genetic polymorphisms of N-Acetyltransferases 1 and 2 and gene-gene interaction in the susceptibility to child‐ hood acute lymphoblastic leukemia. Cancer epidemiology, biomarkers & prevention

ance of preleukemic clone in unaffected twin. Blood 2009; 113(26):6691-4.

with Down syndrome. Pediatric blood & cancer 2005;44(1):8-12.

dren's Oncology Group. British journal of cancer 2004; 91(11):1866-72.

research. Nature reviews. Cancer 2005; 5(4):311-21.

14 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

City. Leukemia & lymphoma 2009; 50(8): 1352–60.

genetic polymorphisms. Blood 1999; 93(5):1496-501.

2000; 9(6):557-62.

330(7503):1279-80.

kemia 2003; 17(9):1905-07.

nal of cancer2009; 101(5):860-4.


[49] Selevan SG, Kimmel CA, Mendola P. Indentify critical windows of exposure for chil‐ dren's health. Environmental health perspectives 2000; 108(Suppl 3):451-455.

[62] Lander ES. Initial impact of the sequencing of the human genome. Nature 2011;

Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

http://dx.doi.org/10.5772/52716

17

[65] Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leuke‐ mia: where are we going and how do we get there? Blood 2012; 120(6):1165-74.

[66] Mejia-Arangure JM,Fajardo-Gutierrez A. Selection by Susceptibility as a Design to Identify Environmental Risk Factors in Children's Acute Leukemia. Epidemiology

[68] Rothman KJ. What is causation. In: Epidemiology. An introduction. New York: Ox‐

[69] Mejia-Arangure JM, Fajardo-Gutierrez A, Perez-Saldivar ML, Gorodezky C, Marti‐ nez-Avalos A, Romero-Guzman L, Campo-Martinez MA, Flores-Lujano J, Salaman‐ ca-Gomez F, Velasquez-Perez L. Magnetic Fields and Acute Leukemia in Children

[70] Ebi K, von Ehrenstein OS, Radon K. Electromagnetic fields. In: Tamburlini G, Ehren‐ stein OV, Bertollini R. Children's health and environment: a review of evidence. En‐ vironmental issue report No. 29. Regional Office for Europe, Germany: World Health

[71] Ecclesiastes 3:1. Holy Bible, New International Version® Anglicized, NIV® Copy‐

[63] Willyard C. Breaking the cancer habit. Nature 2011; 471(7339):S16-S17.

[64] Brower V. Portents of malignancy. Nature 2001; 471(7339):S19-S21.

[67] Popper K. The logic of scientific discovery. London: Routledge 2002

With Down Syndrome. Epidemiology 2007; 18(1):158-61.

470(7333):187-97.

2006; 17(16):S505-S506

ford University Press 2012. p23-37

Organization 2002. p172-87.

right © 1979, 1984, 2011 by Biblica, Inc.®


[49] Selevan SG, Kimmel CA, Mendola P. Indentify critical windows of exposure for chil‐ dren's health. Environmental health perspectives 2000; 108(Suppl 3):451-455.

[50] Anderson LM, Diwan BA, Fear NT, Roman E. Critical windows of exposure for chil‐ dren's health: cancer in human epidemiological studies and neoplasms in experimen‐ tal animal models. Environmental health perspectives 2000; 108(Suppl 3):573-594.

[51] Charnley G, Putzrath RM. Children's health, susceptibility, and regulatory ap‐ proaches to reducing risk from chemical carcinogens. Environmental health perspec‐

[52] Perera FP, Illman SM, Kinney PL, Whyatt RM, Kelvin EA, Shepard P y cols. The chal‐ lenge of preventing environmentally related disease in young children: communitybased research in New York City. Environmental health perspectives 2002; 110(2):

[53] Thomas RD. Age-specific carcinogenesis: Environmental exposure and susceptibility.

[54] Smith A, Lightfoot T, Simpson J, Roman E. Birth weight, sex and childhood cancer: A report from the United Kingdom Childhood Cancer Study. Cancer Epidemiology

[55] Anderson LM, Jones AB, Rice JM. Perinatal carcinogenesis: current directions. British

[56] Ross JA. Environmental and Genetic Susceptibility to MLL-Defined Infant Leukemia. Journal of the National Cancer Institute Monographs 2008;2008(39):83–86.

[57] Kang H, Wilson CS, Harvey RC, Chen IM, Murphy MH, Atlas SR, Bedrick EJ, Devi‐ das M, Carroll AJ, Robinson BW, Stam RW, Valsecchi MG, Pieters R, Heerema NA, Hilden JM, Felix CA, Reaman GH, Camitta B, Winick N, Carroll WL, Dreyer ZE, Hunger SP, Willman CL. Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study. Blood

[58] Pelayo R, Dorantes-Acosta E, Vadillo E, Fuentes-Panana E. From HSC to B-Lym‐ phoid cells in normal and malignant hematopoiesis. In: Pelayo R. (ed.) Advances in

[59] Purizaca J, Meza I, Pelayo R.Early lymphoid development and microenvironmental cues in B-cell acute lymphoblastic leukemia.Archives of medical research 2012; 43(2):

[60] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;

[61] Stratton MR. Exploring the genomes of cancer cells: Progress and promise. Science

hematopoietic stem cell research. Rijeka: In Tech; 2011. p277-98.

Environmental health perspectives1995; 103(Suppl 6):45-48.

16 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

tives 2001; 109(2): 187-192.

197-204.

2009; 33(5):363-7.

2012;119(8):1872-81.

89-101

144(5):646-74.

2011; 331(6024):1553-8.

journal of cancer 1991; 63:1025-8.


**Chapter 2**

**Infectious Etiology of Childhood Acute Lymphoblastic**

Research on the role of infectious agents in the etiology of cancer has grown remarkably in recent decades. A causal association between infection events and the development of differ‐ ent types of cancer has been strongly suggested in epidemiologic studies, while the direct

It is now recognized that between 15 and 20% of all tumors are associated with infection by direct tumorigenic agents [1]. However, the transforming mechanisms of carcinogenic infec‐ tious agents are not restricted to the expression of oncogenes and their ability to modulate the expression and function of oncogenes and anti-oncogenes in target cells. Other routes of transformation have been described, in which, an agent participates through more indirect mechanisms, such as promoting immune suppression or chronic inflammation. Although, in indirect mechanisms of transformation the infectious agent usually does not reside in the cell that will form the tumor mass, it contributes to cancer development making favorable

One of the malignancies proposed to be etiologically related to infection is childhood acute lymphoblastic leukemia (ALL). ALL is a heterogeneous group of hematologic malignancies in which the process of differentiation and limited proliferation that characterizes normal lymphopoiesis is altered and replaced by a malignant clonal expansion of immature lym‐ phocytes. ALL is the most common type of childhood malignancy worldwide, unfortunate‐ ly, little is known about the origin of ALL, some cases are associated with genetic predisposition conferred by Down syndrome, Bloom syndrome, ataxia-telangiectasia, Nij‐ megen breakage syndrome or exposure to environmental agents such as ionizing radiation

and reproduction in any medium, provided the original work is properly cited.

© 2013 Morales-Sánchez and Fuentes-Pananá; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

oncogenic capacity of a set of pathogens has been demonstrated in the laboratory.

**Leukemia, Hypotheses and Evidence**

Additional information is available at the end of the chapter

Abigail Morales-Sánchez and Ezequiel M. Fuentes-Pananá

http://dx.doi.org/10.5772/54455

conditions for tumor initiation or growth.

properly cited.

**1. Introduction**
