Chronic Lymphocytic Leukemia

462 Pages·2012·12.089 MB·English

by  P. Oppezzo

CHRONIC LYMPHOCYTIC
LEUKEMIA

Edited by Pablo Oppezzo
Chronic Lymphocytic Leukemia
Edited by Pablo Oppezzo

Published by InTech
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Copyright © 2012 InTech
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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 [email protected]

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 G0 / 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 VH
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 IgVH 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
IgVH 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 VH genes,
whereas the 13q deletion or a normal karyotype are associated with good prognosis,
early disease and Mut VH 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 IgVH genes, such