title: DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.
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 p21(Cip1) (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.
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Margarida A
authors: MA
authors: Santos
authors: 1] Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors: Robert B
authors: RB
authors: Faryabi
authors: 1] Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors: Aysegul V
authors: AV
authors: Ergen
authors: 1] Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors: Amanda M
authors: AM
authors: Day
authors: 1] Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors: Amy
authors: A
authors: Malhowski
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Andres
authors: A
authors: Canela
authors: The Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Masahiro
authors: M
authors: Onozawa
authors: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Ji-Eun
authors: JE
authors: Lee
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Elsa
authors: E
authors: Callen
authors: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Paula
authors: P
authors: Gutierrez-Martinez
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Hua-Tang
authors: HT
authors: Chen
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Nancy
authors: N
authors: Wong
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Nadia
authors: N
authors: Finkel
authors: Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Aniruddha
authors: A
authors: Deshpande
authors: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Susan
authors: S
authors: Sharrow
authors: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Derrick J
authors: DJ
authors: Rossi
authors: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology and Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Keisuke
authors: K
authors: Ito
authors: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Kai
authors: K
authors: Ge
authors: The Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Peter D
authors: PD
authors: Aplan
authors: Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Scott A
authors: SA
authors: Armstrong
authors: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: André
authors: A
authors: Nussenzweig
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D038042:Myelopoiesis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D017382:Reactive Oxygen Species; D011495:Histone-Lysine N-Methyltransferase; C516439:MLL4 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins