CHRONIC LYMPHOCYTIC LEUKEMIA ppt

CHRONIC LYMPHOCYTIC LEUKEMIA Edited by Pablo Oppezzo           Chronic Lymphocytic Leukemia Edited by Pablo Oppezzo Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 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 Marko Rebrovic Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published February, 2012 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 Chronic Lymphocytic Leukemia, Edited by Pablo Oppezzo p. cm. 978-953-307-881-6  Contents Preface IX Part 1 Introduction 1 Chapter 1 Selected Topics in Chronic Lymphocytic Leukemia Pathogenesis 3 Sergio Bianchi, Guillermo Dighiero and Otto Pritsch Part 2 CLL Biology and Microenvironment 19 Chapter 2 Microenvironment Interactions in Chronic Lymphocytic Leukemia: A Delicate Equilibrium Linking the Quiescent and the Proliferative Pool 21 F. Palacios, C. Abreu, P. Moreno, M. Giordano, R. Gamberale and P. Oppezzo Chapter 3 Dysregulation of Apoptosis and Proliferation in CLL Cells 37 Marcin Wójtowicz and Dariusz Wołowiec Chapter 4 DNA Damage Response/Signaling and Genome (In)Stability as the New Reliable Biological Parameters Defining Clinical Feature of CLL 63 Jozo Delic, Jean-Brice Marteau, Karim Maloum, Florence Nguyen-Khac, Frédéric Davi, Zahia Azgui, Véronique Leblond, Jacques-Louis Binet, Sylvie Chevillard and Hélène Merle-Béral Chapter 5 Current Knowledge of Microarray Analysis for Gene Expression Profiling in Chronic Lymphocytic Leukemia 95 Ida Franiak-Pietryga and Marek Mirowski Chapter 6 Contribution of microRNAs to CLL Biology and Their Potential as New Biomarkers 119 Maria Rosa Garcia-Silva, Maria Catalina Güida and Alfonso Cayota VI Contents Chapter 7 The Biological Relevance of ZAP-70 in CLL 135 Valerie Pede, Ans Rombout, Bruno Verhasselt and Jan Philippé Chapter 8 Pathophysiology of Protein Kinase C Isozymes in Chronic Lymphocytic Leukaemia 153 John C. Allen and Joseph R. Slupsky Chapter 9 The Role of Polymorphisms in Co-Signalling Molecules’ Genes in Susceptibility to B-Cell Chronic Lymphocytic Leukaemia 179 Lidia Karabon and Irena Frydecka Part 3 CLL Animal Models 201 Chapter 10 Mouse Models of Chronic Lymphocytic Leukemia 203 Gema Pérez-Chacón and Juan M. Zapata Chapter 11 Altering microRNA miR15a/16 Levels as Potential Therapy in CLL: Extrapolating from the De Novo NZB Mouse Model 229 Siddha Kasar, Yao Yuan, Chingiz Underbayev, Dan Vollenweider, Matt Hanlon, Victor Chang, Hina Khan and Elizabeth Raveche Part 4 CLL Prognosis 249 Chapter 12 Prognostic Factors in Chronic Lymphoid Leukemia and Identification of New Clinically Relevant Molecular Markers 251 José-Ángel Hernández, Marcos González and Jesús-María Hernández Chapter 13 Genetics of Chronic Lymphocytic Leukemia: Practical Aspects and Prognostic Significance 269 N. Put, I. Wlodarska, P. Vandenberghe and L. Michaux Part 5 CLL Therapy 297 Chapter 14 Immune Response and Immunotherapy in Chronic Lymphocytic Leukemia 299 Leticia Huergo-Zapico, Ana P. Gonzalez-Rodríguez, Juan Contesti, Azahara Fernández-Guizán, Andrea Acebes Huerta, Alejandro López-Soto and Segundo Gonzalez Chapter 15 In Vitro Sensitivity Testing in the Assessment of Anti-CLL Drug Candidates 323 Günter Krause, Mirjam Kuckertz, Susan Kerwien, Michaela Patz and Michael Hallek Contents VII Chapter 16 Interactions of the Platinum(II) Complexes with Nitrogen- and Sulfur-Bonding Bio-Molecules in Chronic Lymphocytic Leukemia 339 Jovana Bogojeski, Biljana Petrović and Živadin D. Bugarčić Chapter 17 Infectious Diseases and Clinical Complications During Treatment in CLL 367 Farhad Abbasi Chapter 18 Emerging Therapies in Chronic Lymphocytic Leukemia 383 Reslan Lina and Dumontet Charles Chapter 19 Heat Shock Proteins in Chronic Lymphocytic Leukaemia 399 Nina C. Dempsey-Hibbert, Christine Hoyle and John H.H. Williams Chapter 20 Present and Future Application of Nanoparticle Based Therapies in B-Chronic Lymphocytic Leukemia (B-CLL) 431 Eduardo Mansilla, Gustavo H. Marin, Luis Núñez, Gustavo Larsen, Nelly Mezzaroba and Paolo Macor  Preface  Chronic lymphocytic leukemia (CLL) follows an extremely variable course with survival ranging from months to decades. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in CLL patients. In particular, the mutational profile of Ig genes and some cytogenetic abnormalities have been found to be important predictors of prognosis in CLL. However, this progress has raised new questions about the biology, prognosis and management of the disease, some of which are addressed here. CLL is characterized by accumulation of CD5 positive monoclonal B cells in primary and secondary lymphoid tissues. It is described as the most common leukemia in the occidental world (4.4-5.4/100.000) [1], whereas it is rare in Asian populations [2]. The existence of mature neoplastic lymphocytes with an abnormally long life span has been a hallmark of this disease but recent data show that the proliferative rates of CLL cells can be higher than previously expected indicating that CLL B cells have a dynamic kinetic behavior [3]. As most circulating CLL B cells are in the G 0 / early G1 phase of the cell cycle, it was long thought that CLL clones hardly proliferate and die infrequently. However, circulating leukemic cells in the peripheral blood are the tip of the iceberg. Clearly the most significant pathophysiological events occur in tissues where leukemic cells: a) are activated by exposure to antigens, although it is still unclear where and how this exposure takes place, b) proliferate in specific niches, (the so-called pseudofollicular proliferation centres) which are not detected in any B-cell malignancy other than CLL, and c) receive the proper T-cell help and interact with stromal cells that favour cell proliferation and accumulation. These observations turn the attention towards the occurrence of different sub-populations inside the tumoral clone in which a homeostatic balance exists in patients with stable lymphocyte counts and good clinical course or an imbalance in patients with rising lymphocyte counts and poor outcome [4]. Different cellular subsets in CLL could receive survival signals from specific microenvironments increasing their proliferative potential and consequently leading to a more aggressive disease. The standard clinical procedures to estimate prognosis are the clinical staging systems developed by Rai and Binet [5,6]. These systems define early (Rai 0, Binet A), intermediate (Rai I/II, Binet B) and advanced (Rai III-V, Binet C) stage disease. However, the high heterogeneity of this disease among individual patients does not X Preface allow us to predict how the disease will evolve. In order to refine outcome prediction for individual patients, there has been intensive work to identify additional clinical and/or biological factors of potential prognostic relevance. Among them, the genetic characteristics of the CLL clone are undoubtedly the most relevant. Molecular genetics of CLL can be divided into two major issues: 1) mutation status of the variable V H genes of immunoglobulin's (Ig), which could be related to the cellular origin of CLL and 2) Genomic aberrations, some of which are involved in the progression and/or refractoriness to treatment. Since B-CLL cells express the CD5 protein on their surface membrane, it was assumed that these cells would behave similarly to CD5 positive B cells in mice (B1a B cell subset) and would not accumulate significant numbers of immunoglobulins (Ig) V gene mutations. However, it was not the case and we now know that somatic mutations do occur in a significant proportion of B-CLL cases. [7]. The presence of these mutations denotes subgroups of patients with markedly different clinical course and outcomes. This important scientific observation has been correlated with a clinical relevant application, since absence of mutations in IgV H is associated with a short survival (unmutated patients -Um-), whereas the presence of mutations in this region is linked with a good prognosis (mutated patients -Mut-) [8]. The biased use of certain IgV H genes and the existence of similarities among Ig rearrangements raise the possibility that an antigenic stimulation could support the malignant cell growth. The other genetic parameter shown to be of pathogenic and clinical relevance in CLL is the presence of genomic aberrations in the leukemic clone. In contrast with what is observed in other B cell malignancies, which typically exhibit balanced chromosomal translocations, the most frequent abnormalities in CLL are mutations, deletions or trisomies. Döhner et al. demonstrated in a series of 325 CLL patients that chromosomal aberrations can be detected in interphase cells by fluorescence in situ hybridization (FISH) in 82% of cases [9]. The most frequent alterations are 13q deletions, observed in 55% of patients, followed by trisomy 12 (18%) and the 11q deletion (16%). The 17p deletion involving the p53 protein is observed less frequently (7%). Interestingly, the presence of a 17p or 11q deletion is associated with poor prognosis and predominates among advanced stages of the disease and among patients displaying Um V H genes, whereas the 13q deletion or a normal karyotype are associated with good prognosis, early disease and Mut V H genes. Based in these studies it is clear that VH mutation status and genomic aberrations are among the strongest currently available parameters and are of independent value to predict outcome in CLL. Despite a common gene expression signature Mut and Um CLL cases differentially express more than 100 genes [10]. Among them, over-expression of genes encoding zeta-chain-associated protein (ZAP-70), lipoprotein lipase (LPL), BCL-7a, dystrophin and gravin are observed in the aggressive Um cases, while stable mutated cases over- express Wnt3, CTLA-4, NRIP1 nuclear receptor gene, ADAM and the transcription factor TCF7 [11]. In addition some evidence indicates that particular IgV H genes, such . CHRONIC LYMPHOCYTIC LEUKEMIA Edited by Pablo Oppezzo           Chronic Lymphocytic Leukemia Edited by Pablo Oppezzo Published. B -Chronic Lymphocytic Leukemia (B-CLL) 431 Eduardo Mansilla, Gustavo H. Marin, Luis Núñez, Gustavo Larsen, Nelly Mezzaroba and Paolo Macor  Preface  Chronic lymphocytic leukemia. features of chronic lymphocytic leukemia B cells. Best Pract Res Clin Haematol 20 (3), 399-413 [4] Caligaris-Cappio, F. (2011) Inflammation, the microenvironment and chronic lymphocytic leukemia.