BCAT1 is a NOTCH1 target and sustains the oncogenic function of NOTCH1
| Autor: | Valeria Tosello, Ludovica Di Martino, Adonia E. Papathanassiu, Silvia Dalla Santa, Marco Pizzi, Lara Mussolin, Jingjing Liu, Pieter van Vlierberghe, Erich Piovan |
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| Jazyk: | angličtina |
| Rok vydání: | 2024 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 999, Iss 1 (2024) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2024.285552 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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