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

Margarida A. Santos, Robert B. Faryabi, Aysegul V. Ergen, Amanda M. Day, Amy Malhowski, Andres Canela, Masahiro Onozawa, Ji Eun Lee, Elsa Callen, Paula Gutierrez-Martinez, Hua Tang Chen, Nancy Wong, Nadia Finkel, Aniruddha Deshpande, Susan Sharrow, Derrick J. Rossi, Keisuke Ito, Kai Ge, Peter D. Aplan, Scott A. ArmstrongAndré Nussenzweig

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103 Scopus citations

Abstract

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, 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, 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 p21Cip1 (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

Original languageEnglish (US)
Pages (from-to)107-111
Number of pages5
JournalNature
Volume514
Issue number7520
DOIs
StatePublished - Oct 2 2014

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    Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., Onozawa, M., Lee, J. E., Callen, E., Gutierrez-Martinez, P., Chen, H. T., Wong, N., Finkel, N., Deshpande, A., Sharrow, S., Rossi, D. J., Ito, K., Ge, K., Aplan, P. D., ... Nussenzweig, A. (2014). DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature, 514(7520), 107-111. https://doi.org/10.1038/nature13483