TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-02, Vol.112 (7), p.2169-2174
• Main Authors: Balatti, Veronica, Rizzotto, Lara, Miller, Cecelia, Palamarchuk, Alexey, Fadda, Paolo, Pandolfo, Rosantony, Rassenti, Laura Z, Hertlein, Erin, Ruppert, Amy S, Lozanski, Arletta, Lozanski, Gerard, Kipps, Thomas J, Byrd, John C, Croce, Carlo M, Pekarsky, Yuri
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cells; Gene Deletion; Gene expression; Humans; Karyotypes; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Lymphoma; MicroRNAs - genetics; Mutation; Pathogenesis; Proto-Oncogene Proteins - genetics; Ribonucleic acid; RNA; Rodents; Tumor Suppressor Protein p53 - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1500010112

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 ( TCL1 ) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3′UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1 . We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19 ⁺ cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676 . Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 ( Tp53 ), and is codeleted with Tp53 , we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression. Significance B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia. We previously found that dysregulation of the T-cell leukemia/lymphoma 1 ( TCL1 ) oncogene is a critical contributing event in the pathogenesis of this disease. In this study we investigated molecular causes of TCL1 overexpression in CLL. We identified miR-3676 as a powerful regulator of TCL1 expression. We found that miR-3676 is down-regulated on all groups of CLLs and mutated in 1% of CLLs. Interestingly, miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 ( Tp53 ), and is codeleted with Tp53 in 17p-deleted CLL. Loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression. Thus, this study uncovers a major mechanism in the pathogenesis of CLL.