**5. Conclusions**

272 Advances in Hematopoietic Stem Cell Research

acute leukemia in adults, affecting roughly three out of 100.000 people. AML patients are predominantly elderly, with a median age at diagnosis of 67 (National Cancer Institute

In AML, there is wide patient-to-patient heterogeneity in the appearance of the leukemic blasts. Conventionally, AML is classified into seven French–American–British (FAB)

The discovery of leukemia-initiating cells in acute myeloid leukemias (AMLs) started with the discovery that the large majority of AML blasts do not proliferate and only a small

A common feature to all AML cases is the arrested aberrant differentiation leading to an accumulation of more than 20% blast cells in the bone marrow (Gilliland & Tallman, 2002). More than 80% of myeloid leukemias are associated with at least one chromosomal rearrangement (Pandolfi, 2001), and over 100 different chromosomal translocations have been cloned (Gilliland & Tallman, 2002). Frequently, these translocations involve genes encoding transcription factors that have been shown to play an important role in hematopoietic lineage development. Thus, alteration of the transcriptional machinery appears to be a common

Clinical investigation and experimental animal models suggest that at least two genetic alterations are required for the clinical manifestation of acute leukemia. According to the model proposed by Gilliland & Tallman (2002), cooperation between class I activating mutations and class II mutations that induce termination of differentiation give rise to AML. The class I mutations, such as mutations in the receptor tyrosine kinase genes FLT3 and KIT, RAS family members, and loss of function of neurofibromin 1, confer proliferative and/or survival advantage to hematopoietic progenitors, typically as a consequence of aberrant activation of signal transduction pathways. The class II mutations lead to a halt in differentiation via

While the LSC appears to share many of the cell surface markers previously identified for HSC such as CD34, CD38, HLA-DR, and CD71, there have been several groups who have reported surface markers that are differentially expressed in the two populations. CD90 or Thy-1 is one marker that has been described to be potentially specific of the LSC compartment. Thy-1 is downregulated in normal hematopoiesis as the most primitive stem cells progress toward the progenitor stage. This finding of the lack of expression on LSC might suggest that the primitive stem cell does not contribute to the primary pathological event, or that Thy-1 expression is downregulated as a result of the leukemogenic events

The interaction between CXCL12 (stromal cell–derived factor-1 alpha) and its receptor CXCR4 on leukemic progenitor cells contributes to their homing to the bone marrow microenvironment. CXCR4 levels are significantly elevated in leukemic cells from patients with AML and CXCR4 expression is associated with poor outcome (Konopleva & Jordan, 2011). Constitutive activation of the nuclear factor kappa B (NF-kB) pathway in primary human AML stem cells provided evidence that NF-kB plays a significant role in the overall survival of LSCs as well as AML cell types in general. This pathway is strongly implicated

as a central target in developing LSC-specific therapies (Konopleva & Jordan, 2011).

subtypes corresponding to the maturation stage of the leukemia (Warner et al., 2004).

mechanism leading to arrested differentiation (Pandolfi, 2001; Tenen, 2003).

interference with transcription factors or co-activators (Frankfurt et al., 2009).

minority is capable of forming new colonies (Testa, 2011).

1975–2007).

(Hope et al., 2003).

Adult hematopoietic stem cells are undifferentiated cells capable of self-renewal and differentiation potential in several cell types that comprise the hematopoietic tissue. These cells have been used in bone marrow transplantation for treatment of hematological malignancies as well as non-hematological diseases. The HSC is the main component in the process of hematopoiesis which, together with the cells that make up the bone marrow stromal environment and other intrinsic and extrinsic factors, orchestrates the entire production of progenitors and terminally differentiated blood cells.

However, when this process of cell production is unbalanced, leading to an exacerbated and uncontrolled proliferation of blood progenitor cells, leukemia may develop.The ultimate challenge in coming years will be to understand the stem cell 'programme', particularly the control of self-renewal, in an attempt to develop novel, stem cell-directed therapies. An improved understanding of clonal evolution will be critical if we are to ensure that cancers are not able to evolve mechanisms to evade the new directed therapies. However, reducing the risk of relapse and minimizing long-term side effects should always remain the ultimate goal of understanding the CSCs.

With little doubt, the leukemia stem cell model has had the greatest clinical impact on our understanding and treatment of Philadelphia chromosome positive leukemias. Effective

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**13** 

*Mexico* 

**From HSC to B-Lymphoid Cells in Normal and** 

**Malignant Hematopoiesis** 

Rosana Pelayo1, Elisa Dorantes-Acosta1,2,

 *Mexican Institute for Social Security, Mexico City* 

*Social Security, Mexico City* 

Eduardo Vadillo1 and Ezequiel Fuentes-Pananá3

*1Oncology Research Unit, Oncology Hospital, Mexican Institute for* 

*2Leukemia Clinic, Mexican Children's Hospital 'Federico Gómez', Mexico City 3Research Unit on Parasitic and Infectious Diseases, Pediatric Hospital,* 

Development of B-lymphoid cells is a highly ordered multi-step process that, in adult mammals, starts in bone marrow in a pool of self-renewing multipotential hematopoietic stem cells, which gradually commit to the lymphoid lineage and advance through high regulated differentiation pathways until formation of mature functional cells. Over the last few years, exceptional advances have been recorded in identifying primitive progenitors that lay the foundations of the lymphoid program while losing myeloid potential, along with patterns of transcriptional activity controlling lineage fate decisions and environmental cues that influence the differentiation pathway during normal hematopoiesis. Multicolor flow cytometry, controlled cell cultures, genetic marking systems, microarray technologies and xenotransplantation approaches are being extensively used to address fundamental questions on this regard. Of special interest is the stem cell research with relevance to hierarchy and early events in malignant lymphopoiesis, and to new insights into perspectives that may allow progress in means to protect and sustain the immune system during chemotherapy, inflammation, infection, and following hematopoietic transplantation. In this book chapter, we focus on the hierarchical structure of the early lymphoid system, the current knowledge about intrinsic and microenvironmental factors regulating the differentiation of lymphoid progenitors, and the emerging research to understand malignant lymphoid

Mature blood cells are constantly replaced from a unique cell population of hematopoietic stem cells (HSC) residing in specialized niches within the bone marrow (BM), where the hematopoietic system is organized as a hierarchy of cell types that gradually lose multiple alternate potentials while commit to lineage fates and gain specialized functions (Baba et

**1. Introduction** 

development.

**2. The early steps in the lymphoid development** 

