In the current study, Hu et al1 find that mice lacking miR-29a/b-1 bicistron have reduced HSC numbers correlating with enhanced HSC proliferation and cell death and reduced multilineage engraftment following competitive bone marrow reconstitution (see figure). Although this mouse strain is deficient in both miR-29-a and miR-29-b1, only expression of miR-29a was able to rescue this hematopoietic phenotype. Providing mechanistic insight, transcriptional profiling of miR-29a/b-1–deficient HSCs uncovered a battery of miR-29 direct targets with relevance to stem cell biology, including Dnmt3a. Importantly, several miR-29a/b1 phenotypes could be partially rescued by crossing miR-29a/b-1 2/2 mice with Dnmt3a 1/2 mice to specifically reduce Dnmt3a levels in HSCs lacking miR-29a/b-1. This provides genetic evidence that this particular DNA methyltransferase, a known regulator of HSCs, 7 is a functionally relevant target of miR-29a in this context. In addition to expanding our understanding of how miR-29a has evolved to modulate HSC biology under physiological circumstances, the connection between miR-29a and Dnmt3a also provides important mechanistic insight into how miR-29a might epigenetically influence AML phenotypes. Dnmt3a acquires loss-of-function somatic mutations that result in reduced DNA methylation in a high percentage of AML patients with intermediate-risk cytogenetic profiles or FLT3 mutations, and is associated with a poor prognosis. 8 As miR-29a directly targets Dnmt3a, 1, 9 this may prove to be an important step during the oncogenic process in certain types of AML.

With the identification of miRNAs that drive malignant phenotypes and recent progress in developing various methods to target specific miRNAs therapeutically, miRNAs such as miR-29a may one day be an effective target to treat AML. However, the decision to pursue miR-29a targeting as a means to mitigate AML might prove to be complicated, as a seemingly paradoxical role for exogenous miR-29 family members in blocking AML cell line growth has also been reported. 10 This implies that the miR-29 family may play varying roles in AML depending upon the cellular context and