microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia

Abstract

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.

MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy

“…In one experiment, lethally irradiated mice were transplanted with miR-29-transduced haematopoietic stem and progenitor cells, resulting in symptoms that were consistent with myeloproliferative disease and a latent progression to AML 58 . A second system specifically evaluated the contribution of overexpressed miR-29a to B-CLL.…”

Genetics of anaplastic large cell lymphoma

“…DUSP22 is a dual-specificity phosphatase that inhibits T-cell receptor signaling in reactive T cells and Jurkat cells by inactivating the mitogen-activated protein kinase (MAPK), ERK2 [25]. Up-regulation of MIR29 micro-RNAs may have oncogenic function in ALCL with DUSP22-FRA7H , as has been proposed in acute myeloid leukemia and breast cancer [26,27]. …”

Probing the complexity of miRNA expression across hematopoiesis

“…For example, our findings on early expression of miR-125 and miR-29a are now functionally explained in great detail by Guo et al 9 and Han et al 10 Large scale miRNA expression studies are not limited by the convenience of the hematopoietic model. We anticipate that future technological developments for the high-throughput analysis of miRNA expression in single cells will be particularly powerful and will find broad application in biological research and diagnostics.…”