Molecular pathogenesis of chronic lymphocytic leukemia
Gianluca Gaidano, … , Robin Foà, Riccardo Dalla-Favera
Gianluca Gaidano, … , Robin Foà, Riccardo Dalla-Favera
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(10):3432-3438. https://doi.org/10.1172/JCI64101.
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Molecular pathogenesis of chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. Many CLL patients carry mutated immuno­globulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. Next-generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy.

Authors

Gianluca Gaidano, Robin Foà, Riccardo Dalla-Favera

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Figure 1

A model for the cellular origin of CLL.

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A model for the cellular origin of CLL. Encounter of naive B cells with ...
Encounter of naive B cells with antigen may proceed either through a T cell–dependent reaction occurring in the GC and leading to the generation of memory B cells that have undergone somatic hypermutation of IGHV genes, or in T cell–independent immune responses that may lead to the formation of antigen-experienced B cells harboring unmutated IGHV genes. CLL, and the preceding MBL phase, may originate from both of these subsets of antigen-experienced B cells. CLL originating from B cells that have experienced somatic hypermutation carry mutated IGHV genes and are defined as M-CLL. Conversely, CLL originating from B cells that have been involved in T cell–independent immune reactions harbor germline IGHV genes and are defined as U-CLL. The emergence and growth of a CLL (or MBL) clone is due to the accumulation of genetic lesions in the neoplastic population as well as interactions of the leukemic cells with antigen through the BCR and with microenvironmental components that promote cell proliferation and inhibit apoptosis.