BAG1 down-regulation increases chemo-sensitivity of acute lymphoblastic leukaemia cells.
Elena MariottoDiana CoralloMarcella PantileEmanuela GiarinMartina PigazziGiuseppe BassoGiampietro ViolaSanja AveicPublished in: Journal of cellular and molecular medicine (2021)
BCL2-associated athanogene-1 (BAG1) is a multi-functional protein that is found deregulated in several solid cancers and in paediatric acute myeloid leukaemia. The investigation of BAG1 isoforms expression and intracellular localization in B-cell acute lymphoblastic leukaemia (B-ALL) patient-derived specimens revealed that BAG1 levels decrease during disease remission, compared to diagnosis, but drastically increase at relapse. In particular, at diagnosis both BAG1-L and BAG1-M isoforms are mainly nuclear, while during remission the localization pattern changes, having BAG1-M almost exclusively in the cytosol indicating its potential cytoprotective role in B-ALL. In addition, knockdown of BAG1/BAG3 induces cell apoptosis and G1-phase cell cycle arrest and, more intriguingly, shapes cell response to chemotherapy. BAG1-depleted cells show an increased sensitivity to the common chemotherapeutic agents, dexamethasone or daunorubicin, and to the BCL2 inhibitor ABT-737. Moreover, the BAG1 inhibitor Thio-2 induces a cytotoxic effect on RS4;11 cells both in vitro and in a zebrafish xenograft model and strongly synergizes with pan-BCL inhibitors. Collectively, these data sustain BAG1 deregulation as a critical event in assuring survival advantage to B-ALL cells.
Keyphrases
- cell cycle arrest
- induced apoptosis
- cell death
- liver failure
- pi k akt
- endoplasmic reticulum stress
- respiratory failure
- oxidative stress
- intensive care unit
- stem cells
- cell proliferation
- immune response
- machine learning
- acute myeloid leukemia
- bone marrow
- hepatitis b virus
- photodynamic therapy
- cancer therapy
- artificial intelligence
- mesenchymal stem cells
- deep learning
- aortic dissection