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

Abstract

Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex2. 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 mutations3. 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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Figure 1: Ncstn deficiency leads to CMML-like disease and a significant enlargement of the GMP progenitor population.
Figure 2: Notch signalling suppresses an extensive myeloid gene expression program through the induction of the transcriptional repressor Hes1.
Figure 3: Ectopic expression of Notch1-IC is able to prevent CMML-like disease in Ncstn / mice.
Figure 4: Novel, loss-of-function Notch pathway mutations in human CMML.

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Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data are deposited in Gene Expression Omnibus of the National Center for Biotechnical Information under accession numbers GSE27794, GSE27799 and GSE27811.

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Acknowledgements

We thank G. Fishel, F. Radtke and R. Kopan for donating mouse strains; P. Lopez and the New York University Flow Facility for cell sorting; and A. Heguy and the Geoffrey Beene Translational Core laboratory for assistance with DNA resequencing. The New York University Cancer Institute Genomics Facility helped with micro-array processing. This work was supported by the National Institutes of Health (RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655 to I.A.; R01CA1328234 to R.L.L. and F.M.; U54CA143798 to F.M.), the Leukemia & Lymphoma Society (to I.A.), the American Cancer Society (to I.A.), the Irma T. Hirschl Trust, the Dana Foundation, The Mallinckrodt Foundation, the Alex’s Lemonade Stand Foundation (to I.A.), and the Fund for Scientific Research Flanders (Fonds Wetenschappelijk Onderzoek) and its Odysseus Research Program (to T.T.). A.E. was supported by the National Cancer Institute (1P01CA97403, Project 2) and a gift from the Berrie Foundation. A.K. was supported by an EU Marie Curie International Re-integration Grant. I.v.D.W. was supported by the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie). S.C. was supported by the Hope Street Kids Foundations and P.O. by the New York University Medical Scientist Training Program. T.T. was supported by the Fonds Wetenschappelijk Onderzoek). O.A.W. was supported by the Clinical Scholars Program at Memorial Sloan Kettering Cancer Center and by the American Society of Hematology. R.L.L. is an Early Career Award recipient of the Howard Hughes Medical Institute and is the Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center. I.A. is a Howard Hughes Medical Institute Early Career Scientist.

Author information

I.A., C.L. and A.K. conceived the study and designed all experiments. A.K. and A.E. helped with experimental planning and generated the Ncstnf/f mice. C.L. performed most of the mouse experiments and in vitro studies aided by P.O., S.B, S.C., T.T. and E.A. R.L.L, O.A.-W. and M.B. performed and analysed human leukaemia sample exon sequencing. H.H. and F.M. helped with disease modelling and computational analysis of disease progression. I.v.D.W. and T.T. performed the human stem cell differentiation assays. C.L. and S.I. analysed mouse disease pathology. J.Z. processed and analysed gene expression data.

Correspondence to Apostolos Klinakis or Iannis Aifantis.

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This file contains Supplementary Figure 1-16 with legends and Supplementary Tables 1-5. (PDF 15542 kb)

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