Molecular pathogenesis of chronic lymphocytic leukemia

• Published in: The Journal of clinical investigation Vol. 122; no. 10; pp. 3432 - 3438
• Main Authors: Gaidano, Gianluca, Foà, Robin, Dalla-Favera, Riccardo
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2012
• Subjects: Animals; Antigens; Antigens - immunology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biomedical research; Cell Lineage; Cell Transformation, Neoplastic; Cells; Chromosome Aberrations; Chronic lymphocytic leukemia; Development and progression; Disease Progression; Gene expression; Gene Expression Profiling; Gene mutations; Genes, Immunoglobulin; Genes, Tumor Suppressor; Genetic aspects; Genomes; Health aspects; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Immunoglobulins; Leukemia; Leukemia, Experimental - genetics; Leukemia, Experimental - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - etiology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytes; Mice; Mice, Transgenic; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - pathology; Older people; Pathogenesis; Physiological aspects; Prognosis; Review Series; Risk factors; Somatic Hypermutation, Immunoglobulin; Transferases; Tumor Suppressor Proteins - genetics; United States; Italy
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI64101

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 immuno-globulin 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.