BCAT1 is a NOTCH1 target and sustains the oncogenic function of NOTCH1
Valeria Tosello,
Ludovica Di Martino,
Adonia E. Papathanassiu,
Silvia Dalla Santa,
Marco Pizzi,
Lara Mussolin,
Jingjing Liu,
Pieter van Vlierberghe,
Erich Piovan
Affiliations
Valeria Tosello
Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua
Ludovica Di Martino
Department of Surgery, Oncology and Gastroenterology, University of Padua
Adonia E. Papathanassiu
Ergon Pharmaceuticals, LLC, Washington DC, United States of America
Silvia Dalla Santa
Department of Surgery, Oncology and Gastroenterology, University of Padua
Marco Pizzi
Surgical Pathology and Cytopathology Unit, Department of Medicine - DIMED, University of Padua
Lara Mussolin
Unit of Onco-hematology, stem cell transplant and gene therapy, Department of Women's and Children's Health, University of Padua
Jingjing Liu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
Pieter van Vlierberghe
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
Erich Piovan
Department of Surgery, Oncology and Gastroenterology, University of Padua; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua
High levels of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) have been associated with tumor aggressiveness and drug resistance in several cancer types. Nevertheless, the mechanistic role of BCAT1 in T-cell acute lymphoblastic leukemia (T-ALL) remains uncertain. We provide evidence that Bcat1 was over-expressed following NOTCH1-induced transformation of leukemic progenitors and that NOTCH1 directly controlled BCAT1 expression by binding to a BCAT1 promoter. Further, using a NOTCH1 gain-of-function retroviral model of T-ALL, mouse cells genetically deficient for Bcat1 showed defects in developing leukemia. In murine T-ALL cells, Bcat1 depletion or inhibition redirected leucine metabolism towards production of 3-hydroxy butyrate (3-HB), an endogenous histone deacetylase inhibitor. Consistently, BCAT1 depleted cells showed altered protein acetylation levels which correlated with a pronounced sensitivity to DNA damaging agents. In human NOTCH1-dependent leukemias, high expression levels of BCAT1 may predispose to worse prognosis. Therapeutically, BCAT1 inhibition specifically synergized with etoposide to eliminate tumors in patient-derived xenograft models suggesting that BCAT1 inhibitors may have a part to play in salvage protocols for refractory T-ALL.
