Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

摘要

Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL鈥揂F4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL鈥揂F4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3鈥?untranslated regions may modulate MLL鈥揂F4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL鈥揂F4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL鈥揂F4 expression in MLL鈥揂F4 ALL samples. Restoration of miR-143 in MLL鈥揂F4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL鈥揂F4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL鈥揂F4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL鈥揂F4-negative primary blasts, which was directly associated with expression of the MLL鈥揂F4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL鈥揂F4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL鈥揂F4 B-cell ALL.