Genomics of Chronic Lymphocytic Leukemia MicroRNAs as New Players With Clinical Significance

Abstract

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in the Western world, is characterized by predominantly nondividing malignant CD5+ B cells overexpressing the anti-apoptotic Bcl2 protein. Significant familial aggregation with largely unknown mode of inheritance has been demonstrated. Until recently little else was known regarding the events leading to CLL initiation and progression. New findings support the view that CLL is a genetic disease where the main alterations occur at the level of transcriptional/post-transcriptional regulation of the malignant cells genome because of deregulations of a new class of genes named microRNAs (miRNAs). miRNA genes miR-15a and miR-16-1, located at 13q14.3, are frequently deleted and/or downregulated in patients with B-cell CLL. Both microRNAs negatively regulate Bcl2 at a post-transcriptional level and this repression is enough to induce apoptosis. Therefore, miR-15 and miR-16 are natural antisense Bcl2 interactors that could be used for therapy of Bcl2-overexpressing tumors. Furthermore, microRNA expression profiles can distinguish normal B cells from malignant B cells in CLL. A unique microRNA signature is associated with prognostic factors such as mutations in the immunoglobulin heavy-chain variable-region gene (IgV(H)) or high expression of the 70-kd zeta-associated protein (ZAP-70+) and disease progression in CLL. Mutations in miRNA transcripts are frequent, some of them germ-line, and may have functional importance and may predispose to CLL and to a spectrum of associated malignancies.