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1528 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1529

ENVIRONMENTAL FACTORS (X-linked inhibitor of apoptosis protein) along with transcription
factors like NF-κB (nuclear factor kappa B), NFAT (nuclear factor
Multiple studies have been conducted in an attempt to identify envi- of activated T cells), and STAT3 (signal transducer and activator of
36
ronmental factors that predispose people to the development of CLL. transcription 3) have been clearly demonstrated in CLL. Additional
These studies have consistently identified a family history of hemato- survival signals are provided by the microenvironment and include cel-
logic malignancies as a strong predictive factor for the development lular factors like nurse-like cells, and various chemokines like CXCR4
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of CLL. In the reported International Lymphoma Epidemiology (C-X-C chemokine receptor type 4) and SDF-1 (stromal cell–derived
7,8
38
Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Proj- factor-1). A combination of these factors results in providing the CLL
ect, detailed correlative studies were performed on a large cohort of cells with a survival and proliferative advantage. CLL B cells exhibit dif-
9
white patients with CLL as compared to normal controls. The Inter- ferential proliferation in the various disease compartments, including
Lymph study identified multiple factors that were associated with the the blood, spleen, and marrow. 39,40 CLL B cells isolated from the blood
presence of CLL, including: (1) family history of a first-degree relative of patients lack proliferative potential in vitro and are restricted to the
with hematologic malignancy including lymphomas, leukemias, and resting phase of the cell cycle. 41,42 These cells also undergo spontaneous
myeloma; (2) a history of working or living on a farm; (3) hairdressers; apoptosis in routine culture conditions. Their survival can be extended
and (4) a history of hepatitis C infection. Factors that were found to be when these cells are cultured on stromal cells or nurse like cells that are
protective include a history of allergies, blood transfusions, sun expo- generally found in the secondary lymphoid organs. 43,44 These secondary
sure, and smoking. CLL is also recognized as a service-connected illness lymphoid organs are generally diffusely infiltrated by the B cells and
among Vietnam War veterans who were exposed to Agent Orange. are potentially the sites of cell division and proliferation. In vivo, the
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Limited data suggests a possible risk of CLL in individuals chronically leukemic cell clones increase by 0.1 to 1 percent per day despite a stable
exposed to electromagnetic fields. 11,12 Radiation exposure, however, has blood lymphocyte count as assessed by elegant heavy water studies. 46
not been shown to correlate with the development of CLL as revealed by
population-based studies on survivors of the Hiroshima atomic bomb
and studies on nuclear reactor workers. 13,14 A smaller study conducted IMMUNE DYSREGULATION
on survivors of the Chernobyl nuclear power plant accident did, how-
ever, suggest a slightly higher incidence of CLL in these people. 15 CLL is characterized by progressive immune dysregulation both in the
47
cellular and humoral compartments. Progression of CLL is associated
with an early increase in the absolute number of circulating T cells and
HEREDITARY FACTORS specifically an increase in the immunosuppressive T-regulatory cells. 48,49
Functional studies on T cells from patients with CLL have also shown
CLL has a strong familial predisposition with up to 10 percent of the T cells to be anergic and with impaired proliferative potential, but
patients with a first- or second-degree relative with CLL and an even with a retained capacity to produce cytokines. Functional defects have
50
higher percentage when also considering individuals with monoclo- also been observed in granulocytes. The leukemic B cells are responsi-
51
nal B-cell lymphocytosis. 16,17 Risk of acquiring CLL is also potentially ble for initiating and propagating the immune dysregulation observed
increased in patients with first-degree relatives with other indolent in the disease by producing immunosuppressive cytokines like trans-
non-Hodgkin lymphomas including lymphoplasmacytic lymphomas. forming growth factor-β (TGF-β) or by downregulating critical surface
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Death-associated protein kinase (DAPK) and CD57 (LEU7) germline molecules required for development of a functional immune system
mutations have been linked to familial predisposition in a single CLL such as CD154 and CD80. 52–54 Moreover, the microenvironment is
family. Association studies have identified multiple putative genes, potentially responsible for developing an immunosuppressive niche
19
polymorphisms, and genetic factors including CD5, CD38, tumor in the lymph nodes and marrow that allow for active immune evasion
20
21
necrosis factor (TNF)-α, and human leukocyte antigen (HLA) haplo- of the leukemic B-cells. Collectively, these cellular defects predispose
22
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types, among others, but definite mechanistic studies demonstrating patients to recurrent opportunistic infections especially with herpes
24
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clear contribution to pathogenesis are lacking.
zoster virus and cytomegalovirus (CMV). 56,57 Defects in class switching
of immunoglobulins and normal B-cell function also result in progres-
DISEASE BIOLOGY sive hypogammaglobulinemia that predisposes patients to recurrent
infections with encapsulated organisms. This may in part be related to
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CLL has varied presentations and complex biology that is the focus of the downregulation of CD154 on CLL B-cells or through CD95 inter-
ongoing studies of particular relevance to the practicing oncologist. action with its ligand. 59,60 Understanding of these putative pathways has
CLL cells are derived from the B-lymphocyte lineage as demonstrated resulted in development of mechanistically relevant targeted therapy. 61
by their expression of the pan–B-cell surface markers including CD19,
and a weaker expression of CD20. 25,26 Furthermore, CLL B cells express
the memory B-cell marker CD27, and also exhibit similar microarray
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profiles, suggesting a potential relationship to the normal memory ROLE OF THE B-CELL RECEPTOR
B cell. 28,29 Most CLL B cells also express κ and λ immunoglobulin light PATHWAY
chains on their surface, along with M and D immunoglobulin heavy
chains. 30,31 These immunoglobulins are often reactive toward self- The B-cell receptor (BCR) plays an integral part in the development and
antigens and polyreactive, 32,33 and may play a role in the survival and maturation of B cells. Constitutive activation of the BCR is one of the most
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expansion of the leukemia cell clone. important survival signals for the propagation of CLL B cells. The sur-
CLL is characterized by gradual accumulation of leukemic face immunoglobulin heterodimer that forms an integral part of the BCR,
cells primarily from defective apoptosis that is partly contributed by is critical for both antigen-dependent and antigen-independent signal-
microenvironment interaction. Overexpression of multiple antiapop- ing through the BCR. 63–65 This signal is transduced through a variety of
totic proteins like BCL-2 (B-cell lymphoma-2), MCL-1 (myeloid cell kinases including LYN (Lck/Yes novel), PI3K (phosphatidylinositol-4,5-
leukemia-1), 34,35 BAK (Bcl-2 homologous antagonist/killer), and XIAP bisphosphate 3-kinase), SYK (spleen tyrosine kinase), and BTK (Bruton

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