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Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death
| Content Provider | Scilit |
|---|---|
| Author | Tregnago, Claudia Ros, Ambra Da Porcù, Elena Benetton, Maddalena Simonato, Manuela Simula, Luca Borella, Giulia Polato, Katia Minuzzo, Sonia Borile, Giulia Cogo, Paola Campello, Silvia Massi, Alessandro Romagnoli, Romeo Buldini, Barbara Locatelli, Franco Pigazzi, Martina |
| Copyright Year | 2020 |
| Description | In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug’s safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509857/pdf |
| Ending Page | 4429 |
| Page Count | 13 |
| Starting Page | 4417 |
| DOI | 10.1182/bloodadvances.2020002001 |
| Journal | Blood advances |
| Issue Number | 18 |
| Volume Number | 4 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2020-09-22 |
| Access Restriction | Open |
| Subject Keyword | Research and Experimental Medicine Safety Cell Death Apoptosis Treatment Survival Hematopoietic Aml Leukemia Mll Af6 Journal: Blood advances (Vol- 128, Issue- 18) |
| Content Type | Text |
| Resource Type | Article |
