Our analysis revealed that, counterintuitive to its oncogenic role, IDH2R140Q actually leads to lower expression of the pro-leukemic Hoxa cluster genes in GMPs but this is counteracted by the loss of Mir142. Recipients of Mir142−/− + IDH2R140Q double mutant HSPCs developed a myeloid leukemia characterized by an expansion of immature myeloid cells and a profound inhibition of normal hematopoiesis resulting in peripheral cytopenia, that was not induced by either Mir142 loss-of-function or IDH2R140Q alone; thus demonstrating that loss of Mir142 unlocks the leukemogenic potential of IDH2R140Q. The gene discussed is MIR142; the disease is myeloid leukemia.