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Contents

**Preface IX**

Chapter 3 **Roles of HTLV-1 Tax** 

Chapter 1 **Adult Human T Cell Leukemia 1**  Jean-Philippe Herbeuval

Chapter 4 **Host Immune System Abnormalities** 

Hitoshi Ando and Yoshihisa Yamano

Hiroaki Morimoto and Junichi Tsukada

Sinisa Dovat and Kimberly J. Payne

Petra Obexer, Judith Hagenbuchner

Markus Holzner and Michael J. Ausserlechner

Chapter 8 **Accumulation of Specific Epigenetic Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma 131** 

Chapter 7 **p16INK4A – Connecting Cell Cycle Control**

Chapter 5 **Constitutive Activation of the JAK/STAT** 

Chapter 6 **Ikaros in T-Cell Leukemia 97**

Chapter 2 **Human T-Cell Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia 25**

Mohammad R. Abbaszadegan and Mehran Gholamin

Mariko Mizuguchi, Toshifumi Hara and Masataka Nakamura

**in Leukemogenesis of Human T-Cells 51**

**Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders 65** Tomoo Sato, Natsumi Araya, Naoko Yagishita,

**and Toll-Like Receptor Signaling Pathways in Adult T-Cell Leukemia/Lymphoma 81** 

Takehiro Higashi, Takefumi Katsuragi, Atsushi Iwashige,

**to Cell Death Regulation in Human Leukemia 115** 

Takashi Oka, Hiaki Sato, Mamoru Ouchida, Atae Utsunomiya, Daisuke Ennishi, Mitsune Tanimoto and Tadashi Yoshino

### Contents

#### **Preface IX**

Chapter 1 **Adult Human T Cell Leukemia 1**  Jean-Philippe Herbeuval Chapter 2 **Human T-Cell Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia 25**  Mohammad R. Abbaszadegan and Mehran Gholamin Chapter 3 **Roles of HTLV-1 Tax in Leukemogenesis of Human T-Cells 51**  Mariko Mizuguchi, Toshifumi Hara and Masataka Nakamura Chapter 4 **Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders 65**  Tomoo Sato, Natsumi Araya, Naoko Yagishita, Hitoshi Ando and Yoshihisa Yamano Chapter 5 **Constitutive Activation of the JAK/STAT and Toll-Like Receptor Signaling Pathways in Adult T-Cell Leukemia/Lymphoma 81**  Takehiro Higashi, Takefumi Katsuragi, Atsushi Iwashige, Hiroaki Morimoto and Junichi Tsukada Chapter 6 **Ikaros in T-Cell Leukemia 97**  Sinisa Dovat and Kimberly J. Payne Chapter 7 **p16INK4A – Connecting Cell Cycle Control to Cell Death Regulation in Human Leukemia 115**  Petra Obexer, Judith Hagenbuchner Markus Holzner and Michael J. Ausserlechner Chapter 8 **Accumulation of Specific Epigenetic Abnormalities During Development and Progression** 

**of T Cell Leukemia/Lymphoma 131**  Takashi Oka, Hiaki Sato, Mamoru Ouchida, Atae Utsunomiya, Daisuke Ennishi, Mitsune Tanimoto and Tadashi Yoshino


### Preface

#### **1. Introduction**

T cell malignancies include a spectrum of diseases. The most common of them are: 1) Adult T-cell leukemia (ATLL); 2) Childhood T-cell Acute lymphoblastic leukemia (T-ALL); 3) Cutaneous T-cell lymphoma – that includes mycosis fungoides and Sezary syndrome; and 4) Anaplastic large cell lymphoma – anaplastic lymphoma kinase (ALK)-positive. Although these diseases are distinct clinical entities, they all pose challenging treatment problems for oncologists. Many of these illnesses carry a poor prognosis, and novel treatment modalities are essential to improve survival. Over the last 10 years, significant progress has been made in understanding the molecular pathogenesis of these diseases, which promises to lead to novel targeted chemotherapeutic agents. The purpose of this book is to provide a comprehensive review of the scientific advances in T-cell malignancies and to highlight the most relevant findings that will help the reader understand both basic mechanisms of the disease and future directions that are likely to lead to novel therapies. In order to assure a thorough approach to these problems, contributors include basic scientists, translational researchers and clinicians who are experts in this field. Thus, the target audience for this book includes both basic scientists who will use this book as a review of the advances in our fundamental knowledge of the molecular mechanisms of T-cell malignancies, as well as clinicians who will use this book as a tool to understand rationales for the development of novel treatments for these diseases.

#### **2. Adult Human T-Cell Leukemia and Molecular Mechansims of HTLV-1**

The first chapter, "Adult Human T cell Leukemia" by Herbeuval J-P., provides an overview of human ATLL. This chapter spans the role of HTLV-1 virus, including its genomic and epidemiological characteristics; the clinical picture and treatment of ATLL, and immune response to HTLV-1 with a brief overview of the role of specific types of immune cells. This chapter gives a comprehensive review of ATLL, with sufficient depth of knowledge for practical oncologists, without extensive molecular mechanistic details of the pathophysiology of the disease.

The subsequent three chapters are primarily concerned with the molecular mechanisms by which HTLV-1 causes ATLL. Chapter 2, "Human T-Cell

#### X Preface

Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia," by Abbaszadegan M.R. and Gholamin M., provides an overview of the structure, epidemiology, function and pathophysiological effects of HTLV-1 in A-TALL. This chapter provides up-to-date knowledge of the first discovered human retrovirus along with its primary molecular functions. In Chapter 3, "Roles of HTLV-1 Tax in Leukemogenesis of Human T-Cells," Nakamura M. focuses on detailed molecular mechanisms of the role of the Tax1 gene of HTLV-1 in malignant transformation and the development of ATLL. The author specifically addresses the role of Tax1 in promoting cell growth, deregulating cellular signaling, and in the modification of apoptosis and cellular immortalization. Chapter 4, "Host Imune System Abnormalities Among Patients with Human T-Lymphothropic Virus Type 1 (HTLV-1)-Associated Disorders" by Yagishita N., Araya N., and Sato T., centers on the immunological abnormalities of HTLV-1-positive patients. Specifically, functional changes in CD4+ T cells and abnormalities of the cytotoxic T lymphocyte (CTL) response, as well as abnormalities of innate immunity following HTLV-1 infection are described.

Preface XI

The last three chapters cover the mechanisms of a common complication of ATLL – hypercalcemia, as well as a novel therapeutic approach for this disease. Chapter 10, "Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma" by Rosol T.J., et al. provides an overview of hypercalcemia of malignancy. The chapter emphasizes the roles of various factors in the pathogenesis of humoral hypercalcemia of malignancies (HHM), the clinical significance of HHM in various T-cell malignancies, and therapeutic approaches to HHM. Chapter 11, "The Role of T-Cell Leukemia Translocation-Associated Gene (TCTA) Protein in Human Osteoclastogenesis" by Nanke Y. et al. concentrates on the mechanism by which the TCTA protein regulates osteoclastogenesis. The role of the receptor activator NF-kB ligand (RANKL) in osteoclastogenesis, and recent discoveries about the role of TCTA as an inhibitor of RANKL-induced osteoclastogenesis is described in detail. Chapter 12, "Retrovirus Infection and Retinoid," Maeda Y et al. describe retinoids as a potential novel treatment agent for ATLL. The growth inhibition effect of All-Trans Retinoic Acid (ATRA), its downregulation of IL-2R/CD25, and its inhibition of NF-kB transcription activity by ATRA are described. The potential clinical use of retinoids for

This book provides an up-to-date overview of advances in our understanding of the pathogenesis of T cell malignancies and will serve as a tool for both basic scientists and clinicians by providing a basis for further studies and an aid in the search for more

**Sinisa Dovat**

*United States of America* 

**Kimberly J. Payne** *Loma Linda University United States of America* 

*Pennsylvania State University College of Medicine* 

**4. Complications of T-Cell Malignancies and Experimental Therapy** 

T-cell malignancies is discussed.

effective therapies for these challenging diseases.

**5. Summary** 

#### **3. Signaling Pathways in T-Cell Malignancies**

The next four chapters describe the role of specific genes or pathways in the pathogenesis of ATLL, T-ALL, and other T-cell malignancies. Chapter 5, "Constitutive Activation of the JAK/STAT and Toll-Like Receptor Signaling Pathways in Adult T-Cell Leukemia/Lymphoma" by Tsukada J., et al., focuses on the functional specificity of these pathways in HTLV-1 infected cells and their role in malignant transformation. In Chapter 6, "The Role of Ikaros in T-ALL," Dovat S. and Payne K.J. dissect the role of the Ikaros (Ikzf1) tumor suppressor gene and its regulatory signal transduction pathways in the control of proliferation in malignant cells. The novel findings that Casein Kinase 2 (CK2) and Protein Phosphatase 1 (PP1) control the ability of Ikaros to regulate tumor suppression in T-cell leukemia are summarized. Chapter 7, "p16INK4A – Connecting Cell Cycle Control to Cell Death Regulation in Human Leukemia" by Ausserlechner M.J. et al., focuses on the role of the INK4 inhibitor protein p16INK4A in the regulation of cell cycle and cell survival in T-ALL. The role of the INK4A gene in the generation of induced pluripotent stem cells and in hematopoietic stem cells is discussed. Chapter 8, "Accumulation of Specific Epigenetic Abnormalities During Development and Progression of T cell Leukemia/Lymphoma" by Yoshino T. et al., describes recent findings on the role of epigenetic changes in the development of T cell leukemia and in cellular proliferation. This chapter summarizes the scientific advances in epigenetic regulation of gene expression related to T cell leukemia/lymphoma, and provides an overview of the role of DNA methylation and histone modifications in the regulation of gene expression. Chapter 9, "Roles of MicroRNA In T-Cell Leukemia" by Tomita M., centers on another emerging field of molecular biology – microRNA and its role in the regulation of gene activity. This chapter gives a nice overview of the mechanism of microRNA action that is easily understandable for both basic scientists and clinicians and describes the role of microRNA in different types of T-cell malignancies.

#### **4. Complications of T-Cell Malignancies and Experimental Therapy**

The last three chapters cover the mechanisms of a common complication of ATLL – hypercalcemia, as well as a novel therapeutic approach for this disease. Chapter 10, "Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma" by Rosol T.J., et al. provides an overview of hypercalcemia of malignancy. The chapter emphasizes the roles of various factors in the pathogenesis of humoral hypercalcemia of malignancies (HHM), the clinical significance of HHM in various T-cell malignancies, and therapeutic approaches to HHM. Chapter 11, "The Role of T-Cell Leukemia Translocation-Associated Gene (TCTA) Protein in Human Osteoclastogenesis" by Nanke Y. et al. concentrates on the mechanism by which the TCTA protein regulates osteoclastogenesis. The role of the receptor activator NF-kB ligand (RANKL) in osteoclastogenesis, and recent discoveries about the role of TCTA as an inhibitor of RANKL-induced osteoclastogenesis is described in detail. Chapter 12, "Retrovirus Infection and Retinoid," Maeda Y et al. describe retinoids as a potential novel treatment agent for ATLL. The growth inhibition effect of All-Trans Retinoic Acid (ATRA), its downregulation of IL-2R/CD25, and its inhibition of NF-kB transcription activity by ATRA are described. The potential clinical use of retinoids for T-cell malignancies is discussed.

#### **5. Summary**

X Preface

infection are described.

malignancies.

**3. Signaling Pathways in T-Cell Malignancies** 

Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia," by Abbaszadegan M.R. and Gholamin M., provides an overview of the structure, epidemiology, function and pathophysiological effects of HTLV-1 in A-TALL. This chapter provides up-to-date knowledge of the first discovered human retrovirus along with its primary molecular functions. In Chapter 3, "Roles of HTLV-1 Tax in Leukemogenesis of Human T-Cells," Nakamura M. focuses on detailed molecular mechanisms of the role of the Tax1 gene of HTLV-1 in malignant transformation and the development of ATLL. The author specifically addresses the role of Tax1 in promoting cell growth, deregulating cellular signaling, and in the modification of apoptosis and cellular immortalization. Chapter 4, "Host Imune System Abnormalities Among Patients with Human T-Lymphothropic Virus Type 1 (HTLV-1)-Associated Disorders" by Yagishita N., Araya N., and Sato T., centers on the immunological abnormalities of HTLV-1-positive patients. Specifically, functional changes in CD4+ T cells and abnormalities of the cytotoxic T lymphocyte (CTL) response, as well as abnormalities of innate immunity following HTLV-1

The next four chapters describe the role of specific genes or pathways in the pathogenesis of ATLL, T-ALL, and other T-cell malignancies. Chapter 5, "Constitutive Activation of the JAK/STAT and Toll-Like Receptor Signaling Pathways in Adult T-Cell Leukemia/Lymphoma" by Tsukada J., et al., focuses on the functional specificity of these pathways in HTLV-1 infected cells and their role in malignant transformation. In Chapter 6, "The Role of Ikaros in T-ALL," Dovat S. and Payne K.J. dissect the role of the Ikaros (Ikzf1) tumor suppressor gene and its regulatory signal transduction pathways in the control of proliferation in malignant cells. The novel findings that Casein Kinase 2 (CK2) and Protein Phosphatase 1 (PP1) control the ability of Ikaros to regulate tumor suppression in T-cell leukemia are summarized. Chapter 7, "p16INK4A – Connecting Cell Cycle Control to Cell Death Regulation in Human Leukemia" by Ausserlechner M.J. et al., focuses on the role of the INK4 inhibitor protein p16INK4A in the regulation of cell cycle and cell survival in T-ALL. The role of the INK4A gene in the generation of induced pluripotent stem cells and in hematopoietic stem cells is discussed. Chapter 8, "Accumulation of Specific Epigenetic Abnormalities During Development and Progression of T cell Leukemia/Lymphoma" by Yoshino T. et al., describes recent findings on the role of epigenetic changes in the development of T cell leukemia and in cellular proliferation. This chapter summarizes the scientific advances in epigenetic regulation of gene expression related to T cell leukemia/lymphoma, and provides an overview of the role of DNA methylation and histone modifications in the regulation of gene expression. Chapter 9, "Roles of MicroRNA In T-Cell Leukemia" by Tomita M., centers on another emerging field of molecular biology – microRNA and its role in the regulation of gene activity. This chapter gives a nice overview of the mechanism of microRNA action that is easily understandable for both basic scientists and clinicians and describes the role of microRNA in different types of T-cell

This book provides an up-to-date overview of advances in our understanding of the pathogenesis of T cell malignancies and will serve as a tool for both basic scientists and clinicians by providing a basis for further studies and an aid in the search for more effective therapies for these challenging diseases.

> **Sinisa Dovat** *Pennsylvania State University College of Medicine United States of America*

> > **Kimberly J. Payne** *Loma Linda University United States of America*

**1** 

*France* 

**Adult Human T Cell Leukemia** 

Human T cell leukemia virus 1 (HTLV-1), the first characterized human retrovirus, has been identified as the causative agent for adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of

HTLV-1 is transmitted intravenously, by sexual contact, or through breast-feeding from mother to child, and epidemiological evidence predicts that ATLL development occurs following childhood infection. ATLL exhibits diverse clinical features: the acute, the subacute or smoldering, the chronic forms and the ATL lymphoma. In the two most aggressive forms (acute leukemia and lymphoma), the tumor syndrome comprises massive lymphadenopathy, hepatosplenomegaly, lytic bone lesions and multiple visceral lesions

HTLV-1 virions infect CD4+ T cells, which represent the main target for HTLV-1 infection in peripheral blood. HTLV-1 associated diseases occur after long periods of virus latency. For years it has been thought that unlike other retroviruses, free virions were poorly infectious. However, a recent study reported that freshly isolated myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) are efficiently and productively infected by cell-free HTLV-1. Furthermore, infected mDC and pDC were able to transfer virions to autologous CD4+ T cells, clearly demonstrating that cell free HTLV-1 can be infectious and target

In 1980 the group of Robert C. Gallo characterized the first human retrovirus, the Human T cell leukemia virus 1 (HTLV-1) (Poiesz, Ruscetti et al., 1980). This virus was recovered from the peripheral blood cells of a patient suffering from adult T-cell-leukemia/lymphoma (ATLL). This form of leukemia is a severe T-cell lymphoma proliferation with bad prognostic due to the resistance of HTLV-1-infected cells to most classical chemotherapeutic

We first describe here the epidemiology, the genomic of HTLV-1 virus and its receptor

HTLV-1 is classified as a complex retrovirus, in the genus delta-retrovirus of the subfamily Orthoretrovirinae. HTLV-1 retrovirus genetic material is composed by a

dendritic cells. Innate immune response against HTLV-1 is poorly documented. We describe here immune response against HTLV-1 and physiological consequences.

**2. The Human T cell leukemia virus 1 (HTLV-1)** 

**2.1 HTLV-1 genomic characteristics** 

HTLV-1-infected cells to most classical chemotherapeutic agents.

**1. Introduction** 

agents.

complex.

with skin and lung infiltration.

*CNRS UMR 8147, Université Paris Descartes* 

Jean-Philippe Herbeuval
