T-CELL LEUKEMIA Edited by Olga Babusikova, Sinisa Dovat and Kimberly J. Payne T-Cell Leukemia Edited by Olga Babusikova, Sinisa Dovat and Kimberly J. Payne Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Used under license from Shutterstock.com First published October, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org T-Cell Leukemia, Edited by Olga Babusikova, Sinisa Dovat and Kimberly J. Payne p. cm. ISBN 978-953-307-400-9 free online editions of InTech Books and Journals can be found at www.intechopen.com 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 p16 INK4A – 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 VI Contents Chapter 9 Roles of MicroRNA in T-Cell Leukemia 169 Mariko Tomita Chapter 10 Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma 181 Sherry T. Shu, Wessel P. Dirksen, Katherine N. Weibaecher and Thomas J. Rosol Chapter 11 The Role of T-Cell Leukemia Translocation-Associated Gene (TCTA) Protein in Human Osteoclastogenesis 207 Shigeru Kotake, Toru Yago, Manabu Kawamoto and Yuki Nanke Chapter 12 Retrovirus Infection and Retinoid 223 Yasuhiro Maeda, Masaya Kawauchi, Chikara Hirase, Terufumi Yamaguchi, Jun-ichi Miyatake and Itaru Matsumura 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. 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, “p16 INK4A – 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. [...]... apoptosis and constitutive expression of Apo2L/TRAIL in human T-cell leukemia virus type 1infected T-cell lines." J Virol 79 (3): 1367-78 Matsuoka, M (2005) "Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL)." Retrovirology 2: 27 Mortreux, F., I Leclercq, et al (2001) "Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences... Yamada, et al (2005) "Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand." Br J Haematol 128 (2): 253-65 Hasegawa, H., Y Yamada, et al (2009) "Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells." Leukemia 23 (11): 2090-101 20 T-Cell Leukemia Heil, F., H Hemmi, et al (2004)... treatment of adult T-cell leukemialymphoma with zidovudine and interferon alfa." N Engl J Med 332 (26): 1749-51 Hermine, O., H Dombret, et al (2004) "Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/ lymphoma." Hematol J 5 (2): 130-4 Hinuma, Y., Y Gotoh, et al (1982) "A retrovirus associated with human adult T-cell leukemia: in vitro... consequences 2 The Human T cell leukemia virus 1 (HTLV-1) 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... children (Manns et al., 1999) We focus in this section on the complex T-cell leukemia/ lymphoma induced by HTLV-1 infection 3.1 HTLV-1 induces T cell leukemia In the late seventies, a group of leukemia patients with characteristic clinical features and particular geographical distribution were identified Uchiyama et al proposed adult T cell leukemia (ATL) as a new disease In 1980 the group of Robert C Gallo... "Identification of genes associated with the progression of adult T cell leukemia (ATL)." Jpn J Cancer Res 91 (11): 1103-10 Koyanagi, Y., Y Itoyama, et al (1993) "In vivo infection of human T-cell leukemia virus type I in non-T cells." Virology 196 (1): 25-33 Kunitomi, A., T Hori, et al (2002) "OX40 signaling renders adult T-cell leukemia cells resistant to Fas-induced apoptosis." Int J Hematol 76 (3):... viruses on cell surface Thus, HTLV-1 may use several strategies to infect target cells However, further studies are needed to clarify the entry of HTLV-1 in patients 6 T-Cell Leukemia 3 The adult T-cell leukemia/ lymphoma (ATLL) Adult T cell leukemia/ lymphoma (ATLL) had been shown to be a consequence of HTLV-1 infection (Hinuma, Gotoh et al., 1982) HTLV-1 infection is also responsible for myelopathy/tropical... Kimberly J Payne Loma Linda University United States of America XI 1 Adult Human T Cell Leukemia Jean-Philippe Herbeuval CNRS UMR 8147, Université Paris Descartes France 1 Introduction 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... Imaizumi, Y., T Kohno, et al (2001) "Possible involvement of interferon regulatory factor 4 (IRF4) in a clinical subtype of adult T-cell leukemia. " Jpn J Cancer Res 92 (12): 1284-92 Imura, A., T Hori, et al (1997) "OX40 expressed on fresh leukemic cells from adult T-cell leukemia patients mediates cell adhesion to vascular endothelial cells: implication for the possible involvement of OX40 in leukemic... (Hermine, Bouscary et al., 1995) The MST was increased in most patients and this therapy constitutes one of the most efficient at the present time 8 T-Cell Leukemia Similarly the combined use of arsenic trioxid and interferon alpha exhibits an anti -leukemia effect in very poor prognosis ATL patients despite a significant toxicity (Hermine, Dombret et al., 2004) Treatment using monoclonal antibodies . 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. needed to clarify the entry of HTLV-1 in patients. T-Cell Leukemia 6 3. The adult T-cell leukemia/ lymphoma (ATLL) Adult T cell leukemia/ lymphoma (ATLL) had been shown to be a consequence. 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