Journal
NATURE
Volume 473, Issue 7346, Pages 230-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09999
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Funding
- National Institutes of Health [RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655, R01CA1328234, U54CA143798]
- Leukemia & Lymphoma Society
- American Cancer Society
- Irma T. Hirschl Trust
- Dana Foundation
- Mallinckrodt Foundation
- Alex's Lemonade Stand Foundation
- Fund for Scientific Research Flanders (Fonds Wetenschappelijk Onderzoek)
- National Cancer Institute [1P01CA97403]
- EU
- Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie)
- Hope Street Kids Foundations
- New York University
- Fonds Wetenschappelijk Onderzoek
- Memorial Sloan Kettering Cancer Center
- American Society of Hematology
- Howard Hughes Medical Institute
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Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types(1). Its activity is controlled by the multisubunit gamma-secretase (gamma SE) complex(2). Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations(3). Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.
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