DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

Histone methyl-transferase MLL4 is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL–AF9 oncogene. Tumour promotion by a DNA repair enzyme Self-renewal, the defining feature of haematopoietic stem cells, is limited by the accumulation of reactive oxygen species and DNA double-strand breaks. Here André Nussenzweig and colleagues investigate whether DNA damage might also constrain leukaemic stem-cell self-renewal and malignant haematopoiesis. They find that the histone methyltransferase MLL4, an enzyme involved in DNA repair, is required for stem cell activity and an aggressive form of acute myeloid leukaemia (AML) harbouring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from AML-related death. These findings uncover an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in AML, and raise the possibility that DNA repair pathway inhibitors may be active against leukaemia. Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells 1 . Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks 2 , 3 , 4 , we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma 5 , 6 , is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL–AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4 −/− MLL–AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL–AF9 blasts, which requires cyclin-dependent kinase inhibitor p21 Cip1 (Cdkn1a) activity. In summary, we have uncovered an unexpected t