MicroRNA miR-29a is an oncomir in myeloid leukemogenesis.

摘要

MicroRNAs (miR) are short non-coding RNAs that negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies; however, there is limited evidence that a single miRNA is sufficient to induce cancer. Herein, we demonstrate that miR-29a is highly expressed in human and mouse hematopoietic stem cells (HSC) and human acute myeloid leukemia (AML) blasts but, down-regulated in normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD). During the MPD, miR-29a alters the composition of the most immature hematopoietic cells, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). Furthermore, mice with miR-29a induced MPD progresses to acute myeloid leukemia (AML). The resulting AML contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators down-regulated in miR-29a expressing cells compared to wild type. We have identified Hbp1 as a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype in vivo, suggesting that additional genes are involved in the leukemogenic activity of miR-29a. These data indicate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid expansion. Moreover, they also establish that aberrant expression of a single miRNA is sufficient to drive leukemogenesis, and suggest that therapeutic targeting of microRNAs may be an effective means of treating AML.