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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 Trp53is responsible for ICL-induced bone marrow failure and that loss of Trp53is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3pand miR-199a-3pwith age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3pstrongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3pactivity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3pfunctions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3pcaused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuRfor miR-139-3pand Prdx6, Runx1, and Suz12for 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-139-3pand miR-199a-3pare involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors.

The proto-oncogene EVI1(ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)–rearranged leukemias are EVI1pos. High EVI1expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELLfusion genes. In addition, we present evidence that EVI1posMLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1negMLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1expression on transformation of Evi1posHSCs. MLL-AF9 does not activate Evi1expression in MLL-AF9–transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1neg. Moreover, shRNA-mediated knockdown of Evi1in an Evi1posMLL-AF9mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1provides a growth-promoting signal. Using the Evi1posMLL-AF9mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1expression. We conclude that EVI1is a critical player in tumor growth in a subset of MLL-rearranged AMLs.