MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Xiao-Shuang Wang,　Jia-Nan Gong, Jia Yu, Fang Wang, Xin-Hua Zhang, Xiao-Lin Yin, Zhen-Qing Tan, Zi-Mian Luo, Gui-Hua Yang, Chao Shen, Jun-Wu Zhang

Blood published ahead of print April 4, 2012, doi:10.1182/blood-2011-10-385716

While microRNAs (miRNAs) are increasingly linked to various physiological processes, including hematpoiesis, their function in the myeloid development is poorly understood. We detected up-regulation of miR-29a and miR-142-3p during myeloid differentiation in leukemia cell lines and CD34+ hematopoietic stem/progenitor cells (HSPCs). By gain-of-function and loss-of-function experiments, we demonstrated that both miRNAs promote the phorbol 12-myristate 13-acetate-induced monocytic and all-trans-retinoic acid-induced granulocytic differentiation of HL-60,　THP-1 or NB4 cells. Both the miRNAs directly inhibited cyclin T2, preventing the release of hypophosphorylated retinoblastoma and resulting in induction of monocytic differentiation. Additionally, a target of miR-29a, cyclin-dependent kinase 6, and a target of miR-142-3p, TGF-beta-activated kinase 1/MAP3K7 binding protein 2, are involved in the regulation of both monocytic and granulocytic differentiation. A significant decrease of miR-29a and 142-3p levels and an obvious increase in their target protein levels were also observed in blasts from acute myeloid leukemia (AML). By lentivirus-mediated gene transfer, we demonstrated that enforced expression of either miR-29a or miR-142-3p in HSPCs from healthy controls and AML patients down-regulated expression of their targets and promoted myeloid differentiation. These findings confirm that miR-29a and miR-142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in AML development.