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Alemdehy, Mir Farshid; Haanstra, Jurgen R.; de Looper, Hans W.J.; van Strien, Paulina M.H.; Verhagen-Oldenampsen, Judith; Caljouw, Yvette; Sanders, Mathijs A.; Hoogenboezem, Remco; de Ru, Arnoud H.; Janssen, George M.C.; Smetsers, Stephanie E.; Bierings, Marc B.; van Veelen, Peter A.; von Lindern, Marieke; Touw, Ivo P.; Erkeland, Stefan J.
Blood, 06/2015, Letnik: 125, Številka: 25Journal Article
Interstrand crosslinks (ICLs) are toxic DNA lesions that cause severe genomic damage during replication, especially in Fanconi anemia pathway-deficient cells. This results in progressive bone marrow failure and predisposes to acute myeloid leukemia (AML). The molecular mechanisms responsible for these defects are largely unknown. Using Ercc1-deficient mice, we show that Trp53 is responsible for ICL-induced bone marrow failure and that loss of Trp53 is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3p and miR-199a-3p with age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3p strongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3p activity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3p functions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3p caused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuR for miR-139-3p and Prdx6, Runx1, and Suz12 for miR-199a-3p. The latter genes have previously been implicated as tumor suppressors in de novo and secondary AML. These findings show that, in addition to TRP53-controlled mechanisms, miR-139-3p and miR-199a-3p are involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors. •miR-139-3p and miR-199a-3p, induced by ICL-induced damage, respectively, cause a loss and gain of hematopoietic progenitors.•miR-199a-3p is an onco-microRNA (onco-miR) causing AML in a Cebpa-deficient mouse model. Target genes of miR-199a-3p include PRDX6, RUNX1, and SUZ12.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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