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MicroRNA-650 Expression Is Influenced By Immunoglobulin Gene Rearrangement And Affects The Biology Of Chronic Lymphocytic Leukemia

Marek Mraz, Dasa Dolezalova, Karla Plevova, Katerina Stano Kozubik, Veronika Mayerova, Katerina Cerna, Katerina Musilova, Boris Tichy, Sarka Pavlova, Marek Borsky, Jan Verner, Michael Doubek, Yvona Brychtova, Martin Trbusek, Ales Hampl, Jiri Mayer, Sarka Pospisilova

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AbstractMicroRNAs (miRNAs) play a key role in chronic lymphocytic leukemia as well as in normal B cells. Notably, miRNA gene encoding miR-650 and its homologs overlap with several variable (V) subgenes coding for lambda immunoglobulin (IgLλ). Recent studies describe the role of miR-650 in solid tumors, but its role in chronic lymphocytic leukemia (CLL) has not yet been studied. Our experiments demonstrate that miR-650 expression is regulated by coupled expression with its host gene for IgLλ. This coupling provides a unique yet unobserved mechanism for microRNA gene regulation. We determine that higher expression of miR-650 is associated with a favorable CLL prognosis and influences the proliferation capacity of B cells. We also establish that in B cells, miR-650 targets proteins important in cell proliferation and survival: cyclin dependent kinase 1 (CDK1), inhibitor of growth 4 (ING4), and early B-cell factor 3 (EBF3). This study underscores the importance of miR-650 in CLL biology and normal B-cell physiology.