Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2.

Beatrice Salvatori (1) , Ilaria Iosue (2) , Nkerorema Djodji Damas (1) , Arianna Mangiavacchi (1) , Sabina Chiaretti (3) , Monica Messina (3) , Fabrizio Padula (4) , Anna Guarini (3) , Irene Bozzoni (5, 1) , Francesco Fazi (6) , Alessandro Fatica (1)

1 Department of Biology and Biotechnology "Charles Darwin"
2 Section of Histology and Medical Embriology, DAHFMO
3 Division of Hematology, Department of Cellular Biotechnologies and Hematology
4 DAHFMO - Department of Anatomy, Histology, Forensic Medicine and Orthopedic [Roma]
5 CNR | IBPM - CNR Istituto di Biologia e Patologia Molecolari [Roma]
6 Department of Medical Surgical Sciences and Biotechnologies

Increased expression or aberrant activation of c-Myc plays an important role in leukemogenesis. Here, we show that in acute myeloid leukemia (AML), c-Myc directly controls the expression of EZH2, a component of the Polycomb repressive complex 2, and miR-26a. miR-26a is downregulated in primary blasts from AML patients and, during myeloid differentiation of AML cells, is induced together with a decrease in c-Myc and Ezh2 levels. Previously, EZH2 was shown to be regulated by miR-26a at the translational levels in lymphomas. However, we demonstrate that in AML, the variation of EZH2 mainly depends on c-Myc transcriptional control. We also show that enforced expression of miR-26a in AML cells is able to inhibit cell cycle progression by downregulating cyclin E2 expression. In addition, increased levels of miR-26a potentiate the antiproliferative effects of 1,25-dihydroxyvitamin D(3) (VitD) and stimulate myeloid differentiation. Our results identify new molecular targets of c-Myc in AML and highlight miR-26a attractiveness as a therapeutic target in leukemia.

Domaines: Cancer; Biochimie, Biologie Moléculaire

Beatrice Salvatori, Ilaria Iosue, Nkerorema Djodji Damas, Arianna Mangiavacchi, Sabina Chiaretti, et al.. Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2.. Genes and Cancer, 2011, 2 (5), pp.585-92. ⟨10.1177/1947601911416357⟩. ⟨pasteur-00976767⟩