Apostolos Klinakis 1 , # , Camille Lobry 2 , Omar Abdel-Wahab 3 , Philmo Oh 2 , Hiroshi Haeno 4 , Silvia Buonamici 2 , 8 , Inge van De Walle 5 , Severine Cathelin 2 , Thomas Trimarchi 2 , Elisa Araldi 2 , Cynthia Liu 2 , Sherif Ibrahim 2 , Miroslav Beran 6 , Jiri Zavadil 7 , Argiris Efstratiadis 1 , Tom Taghon 5 , Franziska Michor 4 , Ross L. Levine 3 , Iannis Aifantis 2 , #
12 November 2011
Notch signaling is a central regulator of differentiation in a variety of organisms and tissue types 1 . Its activity is controlled by the multi-subunit γ–secretase complex (γSE) complex 2 . Although Notch signaling can play both oncogenic and tumor suppressor roles in solid tumors, in the hematopoietic system, it is exclusively oncogenic, notably in T cell acute lymphoblastic leukemia (T-ALL), a disease characterized by Notch1 activating mutations 3 . Here we identify novel somatic inactivating Notch pathway mutations in a fraction of chronic myelomonocytic leukemia (CMML) patients. Inactivation of Notch signaling in mouse hematopoietic stem cells (HSC) resulted in an aberrant accumulation of granulocyte/monocyte progenitors (GMP), extramedullary hematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling 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 signaling during early hematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumor-promoting and suppressive roles within the same tissue.