MYELOID LEUKEMIA – BASIC MECHANISMS OF LEUKEMOGENESIS docx

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MYELOID LEUKEMIA – BASIC MECHANISMS OF LEUKEMOGENESIS docx

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MYELOID LEUKEMIA BASIC MECHANISMS OF LEUKEMOGENESIS Edited by Steffen Koschmieder and Utz Krug Myeloid Leukemia Basic Mechanisms of Leukemogenesis Edited by Steffen Koschmieder and Utz Krug 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 allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. 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. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Ivana Zec Technical Editor Teodora Smiljanic Cover Designer InTech Design Team Image Copyright Eraxion, 2011. First published December, 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 Myeloid Leukemia Basic Mechanisms of Leukemogenesis, Edited by Steffen Koschmieder and Utz Krug p. cm. ISBN 978-953-307-789-5 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Chapter 1 BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy 1 Katarzyna Piwocka, Kamila Wolanin, Monika Kusio-Kobialka and Paulina Podszywalow-Bartnicka Chapter 2 BCR/ABL1 Extra Fusions in Patients with Chronic Myeloid Leukaemia (CML) 27 Maria Teresa Vargas Chapter 3 Causative Factors Involved in Development of Resistance to Tyrosine Kinase Inhibition and Novel Strategies Designed to Override This Resistance 41 Ellen Weisberg and James D. Griffin Chapter 4 De Novo Acquisition of BCR-ABL Mutations for CML Acquired Resistance 69 WenYong Chen, Hongfeng Yuan and Zhiqiang Wang Chapter 5 Targeting the Chronic Myeloid Leukemia Stem Cell: A Paradigm for the Curative Treatment of Human Malignancies 85 Adrian Woolfson and Xiaoyan Jiang Chapter 6 The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia 111 Ignacio Pérez-Roger and María Pilar Albero Chapter 7 Ser/Thr Phosphatases: The New Frontier for Myeloid Leukemia Therapy? 123 Amanda M. Smith, Kathryn G. Roberts and Nicole M. Verrills VI Contents Chapter 8 Role of JAK2 Beyond Myeloproliferative Neoplasms (MPNs): Rationale for Targeting the JAK-STAT Pathway in Other Hematological Malignancies and Solid Tumors 149 Theresa M. McDevitt and Matthew V. Lorenzi Chapter 9 Genetic Alterations and Their Clinical Implications in Acute Myeloid Leukemia 163 Hsin-An Hou, Wen-Chien Chou and Hwei-Fang Tien Chapter 10 Bone Marrow Microenvironment in the Pathogenesis of AML 185 Olga Blau Chapter 11 Distinct Inhibitory Effect of TGFβ on the Growth of Human Myeloid Leukemia Cells 197 Xiao Tang Hu Chapter 12 Novel Targets in Myelogenous Leukemia: The Id Family of Proteins 215 Kimberly D. Klarmann, Ming Ji, Huajie Li, Ande Satyanarayana, Wonil Kim, Emily Bowers, Bjorg Gudmundsdottir and Jonathan R. Keller Chapter 13 PU.1, a Versatile Transcription Factor and a Suppressor of Myeloid Leukemia 239 Shinichiro Takahashi Chapter 14 Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL) 263 Valeria Bertagnolo, Federica Brugnoli and Silvano Capitani Chapter 15 p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia 289 Joanna Fares, Linda Wolff and Juraj Bies Chapter 16 New Molecular Markers in Acute Myeloid Leukemia 313 Silvia de la Iglesia Iñigo, María Teresa Gómez Casares, Carmen Elsa López Jorge, Jezabel López Brito and Pedro Martin Cabrera Chapter 17 Analysis of Leukemogenic Gene Products in Hematopoietic Progenitor Cells 339 Julia Schanda, Reinhard Henschler, Manuel Grez and Christian Wichmann Chapter 18 Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy 363 Emma Lång and Stig Ove Bøe Contents VII Chapter 19 The Association of the DNA Repair Genes with Acute Myeloid Leukemia: The Susceptibility and the Outcome After Therapy 385 Claudia Bănescu, Carmen Duicu and Minodora Dobreanu Chapter 20 Apoptosis and Apoptosis Modulators in Myeloid Leukemia 409 Maha Abdullah and Zainina Seman Chapter 21 Role of Signaling Pathways in Acute Myeloid Leukemia 429 Maha Abdullah and Zainina Seman Chapter 22 Epigenetic Changes Associated with Chromosomal Translocation in Leukemia 449 Soraya Gutierrez, Amjad Javed, Janet Stein, Gary Stein, Sandra Nicovani, Valentina Fernandez, Ricardo Alarcon, Marcela Stuardo, Milka Martinez, Marcela Hinojosa and Boris Rebolledo-Jaramillo Chapter 23 Myeloid Leukemia: A Molecular Focus on Etiology and Risk Within Africa 465 Muntaser E. Ibrahim and Emad-Aldin I. Osman Preface Myeloid leukemias have been studied for decades, and considerable progress has been made in the elucidation of critical pathogenetic factors including transcription factor networks and signaling pathways and in the diagnosis and treatment of these leukemias. However, while the prognosis of a fraction of patients (particularly those with chronic myeloid leukemia in chronic phase) has improved dramatically with the advent of novel rationally designed therapies, the prognosis of many other patients (i.e. with most subtypes of acute myeloid leukemia) has not improved to the same degree and have been compounded by the fact that molecular targeted therapies are expensive and are not readily available in all parts of the world. The intention of this book is to provide a global scope on these issues. Following an open call, authors were invited to propose topics and send in an abstract of the chapter they wanted to contribute. After selection of appropriate abstracts, full chapters were provided and reviewed. Revised chapters were again reviewed and final chapters selected for publication. The topics of the present book focus on basic mechanisms of leukemogenesis and cover the following:  Chromosomal instability and DNA repair in CML and AML  Novel BCR-ABL1 fusions  Mechanisms of resistance to tyrosine kinase inhibitors and strategies how to overcome these  Novel targets at the cellular and molecular level, including CML stem cells, proteasome inhibitors, and activators of phosphatases  Genetic Alterations and new molecular markers in AML, including Acute Promyelocytic Leukemia  The role of the bone marrow microenvironment and TGFß in the pathogenesis of AML  Hematopoietic transcription factors and tumor suppressors, including the Id proteins, PU.1, Vav1, and p15INK4b  Apoptosis and Apoptosis Modulators in Myeloid Leukemia  Functional Analysis of Leukemogenic Gene Products in Hematopoietic Progenitor Cells X Preface  Role of Signaling Pathways in Myeloid Leukemia, including BCR-ABL1 and mutant JAK2  Epigenetic Changes Associated with Chromosomal Translocation in Leukemia  Etiology and Risk factors of AML in Africa Each chapter is a sole-standing publication that reflects each author´s interpretation of the data. However, the unifying theme is myeloid leukemia. Thus, the book displays a multi-facetted picture of our current understanding of myeloid leukemia pathogenesis. In addition, the open access structure of the book will guarantee wide- spread access even in cases where resources required for subscription to more expensive scientific journals or books are limited. We encourage the readers to send their comments. This is an exciting new way of discussing science and to support the effort of increasing the alertness and education of patients and physicians all around the globe. Prof. Dr. Steffen Koschmieder Department of Medicine (Oncology, Hematology, and Stem Cell Transplantation) at the University of Aachen, Germany Dr. Utz Krug Department of Medicine (Hematology, Oncology, Hemostaseology, and Pulmonology) at the University of Münster, Germany [...]... role of BCR-ABL-mediated defects in the mechanisms controlling cell division as well as the role of BRCA1 in the development of aneuploidy in CML 2.1 Centrosomal multiplication Centrosomes are small organelles with a crucial role in the formation of bipolar mitotic spindle, which is necessary for the accurate segregation of chromosomes (Fukasawa, 2007; 4 Myeloid Leukemia Basic Mechanisms of Leukemogenesis. .. Expression of the p210BCR-ABL oncoprotein drives centrosomal hypertrophy and clonal evolution in human U937 cells Leukemia 21(9): 1971-6 20 Myeloid Leukemia Basic Mechanisms of Leukemogenesis Giehl, M., Fabarius, A., Frank, O., Hochhaus, A., Hafner, M., Hehlmann, R.&Seifarth, W (2005) Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability Leukemia. .. genomic instability and finally an increased risk of cancerogenesis Thus, we postulate that the decrease of BRCA1 caused by BCR-ABL could have tremendous consequences due to defective control of genomic stability The role of BRCA1 in the regulation of the DNA 10 Myeloid Leukemia Basic Mechanisms of Leukemogenesis damage response and cell cycle checkpoint control has been already well explained (Huen... 2 Proposed scheme of the mechanisms influenced by BCR-ABL-mediated BRCA1 downregulation; role in the genomic instability and generation of aneuploid cells 5 Therapeutic targeting of mitosis in CML cells The effects of the improper control of mitosis in the development and progression of leukemias, including chronic myeloid leukemia has been already described above The importance of these processes... phosphorylation of BubR1 and finally, regulates chromosome segregation, cytokinesis and mitotic exit PLK1, similarly to other mitotic kinases has been shown to be upregulated in cancers, including lymphomas Studies of a big group of non-Hodgkin’s lymphoma (NHLs) patients presented that the level of PLK1 expression was significantly lower in low-grade NHLs than 8 Myeloid Leukemia Basic Mechanisms of Leukemogenesis. .. compound curcumin, which has been shown as a broadly acting, very potent anticancer agent, we found that it affects the CPC proteins and induces mitotic catastrophe, however without polyploidization Curcumin decreased the level of survivin and caused unproper localization of Aurora B, leading to perturbances in mitosis and defective cytokinesis 16 Myeloid Leukemia Basic Mechanisms of Leukemogenesis. .. BRCA1 in different types of cancers The lack of Nlp protein led to centrosome amplification, aberrant chromosome segregation, cytokinesis failure and appearance of miltinuclei, thus resembling the phenotype upon BRCA1 disruption Recent studies showed that Nlp is recruited by the Aurora B protein and localizes at the midbody during 14 Myeloid Leukemia Basic Mechanisms of Leukemogenesis cytokinesis,... 27-34 24 Myeloid Leukemia Basic Mechanisms of Leukemogenesis Sankaran, S., Starita, L M., Groen, A C., Ko, M J.&Parvin, J D (2005) Centrosomal microtubule nucleation activity is inhibited by BRCA1-dependent ubiquitination Mol Cell Biol 25(19): 8656-68 Sankaran, S., Starita, L M., Simons, A M.&Parvin, J D (2006) Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome... p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis J Biol Chem 279(3): 2077-84 18 Myeloid Leukemia Basic Mechanisms of Leukemogenesis Benezra, M., Chevallier, N., Morrison, D J., MacLachlan, T K., El-Deiry, W S.&Licht, J D (2003) BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit J Biol Chem 278(29): 26333-41... reversed by imatinib treatment, resulting in 12 Myeloid Leukemia Basic Mechanisms of Leukemogenesis BRCA1 upregulation In ovarian cancer it was suggested that BRCA1 can act as a predictive marker of response to chemotherapy (Quinn et al., 2009) and dysfunctional BRCA1 resulted in resistance to taxanes and other chemotherapeutics On the other hand, reconstitution of BRCA1 into ovarian cancer cells, carrying . MYELOID LEUKEMIA – BASIC MECHANISMS OF LEUKEMOGENESIS Edited by Steffen Koschmieder and Utz Krug Myeloid Leukemia – Basic Mechanisms of Leukemogenesis. role in the formation of bipolar mitotic spindle, which is necessary for the accurate segregation of chromosomes (Fukasawa, 2007; Myeloid Leukemia – Basic Mechanisms of Leukemogenesis 4. Studies of a big group of non-Hodgkin’s lymphoma (NHLs) patients presented that the level of PLK1 expression was significantly lower in low-grade NHLs than Myeloid Leukemia – Basic Mechanisms of

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  • 00 preface_ Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

  • 01_ BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

  • 02_ BCR/ABL1 Extra Fusions in Patients with Chronic Myeloid Leukaemia (CML)

  • 03_ Causative Factors Involved in Development of Resistance to Tyrosine Kinase Inhibition and Novel Strategies Designed to Override This Resistance

  • 04_ De Novo Acquisition of BCR-ABL Mutations for CML Acquired Resistance

  • 05_Targeting the Chronic Myeloid Leukemia Stem Cell: A Paradigm for the Curative Treatment of Human Malignancies

  • 06_ The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia

  • 07_ Ser/Thr Phosphatases: The New Frontier for Myeloid Leukemia Therapy?

  • 08_ Role of JAK2 Beyond Myeloproliferative Neoplasms (MPNs): Rationale for Targeting the JAK-STAT Pathway in Other Hematological Malignancies and Solid Tumors

  • 09_Genetic Alterations and Their Clinical Implications in Acute Myeloid Leukemia

  • 10_ Bone Marrow Microenvironment in the Pathogenesis of AML

  • 11_ Distinct Inhibitory Effect of TGFβ on the Growth of Human Myeloid Leukemia Cells

  • 12_Novel Targets in Myelogenous Leukemia: The Id Family of Proteins

  • 13_ PU.1, a Versatile Transcription Factor and a Suppressor of Myeloid Leukemia

  • 14_ Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

  • 15_ p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

  • 16_ New Molecular Markers in Acute Myeloid Leukemia

  • 17_ Analysis of Leukemogenic Gene Products in Hematopoietic Progenitor Cells

  • 18_ Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy

  • 19_ The Association of the DNA Repair Genes with Acute Myeloid Leukemia: The Susceptibility and the Outcome After Therapy

  • 20_ Apoptosis and Apoptosis Modulators in Myeloid Leukemia

  • 21_ Role of Signaling Pathways in Acute Myeloid Leukemia

  • 22_ Epigenetic Changes Associated with Chromosomal Translocation in Leukemia

  • 23_ Myeloid Leukemia: A Molecular Focus on Etiology and Risk Within Africa

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