A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia

Apostolos Klinakis, Camille Lobry, Omar Abdel-Wahab, Philmo Oh, Hiroshi Haeno, Silvia Buonamici, Inge Van De Walle, Severine Cathelin, Thomas Trimarchi, Elisa Araldi, Cynthia Liu, Sherif Ibrahim, Miroslav Beran, Jiri Zavadil, Argiris Efstratiadis, Tom Taghon, Franziska Michor, Ross L. Levine, Iannis Aifantis

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265 Citations (Scopus)

Abstract

Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit Î 3-secretase (γSE) complex. 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. 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.

Original languageEnglish
Pages (from-to)230-233
Number of pages4
JournalNature
Volume473
Issue number7346
DOIs
Publication statusPublished - May 12 2011

All Science Journal Classification (ASJC) codes

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    Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., Van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., & Aifantis, I. (2011). A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature, 473(7346), 230-233. https://doi.org/10.1038/nature09999