Notch1-driven transcriptional changes in a mouse model of T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we used a mouse model of T-ALL through the overexpression of the intarcellular transcriptionally active part of Notch1 (N1-IC). This model faithfully recapitulates the major characteristics of the human disease. Comparison of the leukemic cells from peripheral tumors(thymoma) of this mouse model to normal thymic cells Double Positive (DP) for the markers CD4 and CD8 that express very low levels of Notch1 showed major expression changes in pathways controlling the transition from physiology to disease. Further correlation of the data to ChIP-Seq data from the same cell populations led us to identify a hitherto unknown antagonism of the Notch1 oncogenic pathway and the polycomb complex (PRC2) in leukemia. Importantly exome sequencing in primary samples from human patients with T-ALL revealed that the PRC2 complex is frequently mutated and inactivated, further supporting the tumor suppressor role of the complex in this disease.

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Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, Asp P, Hadler M, Rigo I, De Keersmaecker K, Patel J, Huynh T, Utro F, Poglio S, Samon JB, Paietta E, Racevskis J, Rowe JM, Rabadan R, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A, Aifantis I