Model of how miRNAs control the balance between cell loss, cell survival and expansion, and leukemogenesis during BM stress. During homeostasis, miR-139-3p and miR-199a-3p are expressed at detectable levels in hematopoietic progenitors. The activity of TRP53, miR-139-3p, and miR-199a-3p is induced by ICLs. TRP53 and miR-139 causes the loss of HSPCs, whereas elevated levels of miR-199a-3p only partially compensate cell loss by stimulating HSPC proliferation. Targets of miR-139-3p and miR-199a-3p, Suz12, Runx1, Pon2, and Prdx6 and HuR are downregulated at this stage. Trp53 and miR-139-3p are lost in leukemias, whereas miR-199a-3p is highly expressed. miR-199a-3p is an onco-miR and drives oncogenic transformation of HSPCs toward leukemia.