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Shah K, Nasimian A, Ahmed M, Al Ashiri L, Denison L, Sime W, Bendak K, Kolosenko I, Siino V, Levander F, Palm-Apergi C, Massoumi R, Lock RB, Kazi JU
Blood Cancer J 13 (1) 139 [2023-09-07; online 2023-09-07]
The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism.
Bioinformatics Support and Infrastructure [Collaborative]
Bioinformatics Support, Infrastructure and Training [Collaborative]
PubMed 37679323
DOI 10.1038/s41408-023-00914-7
Crossref 10.1038/s41408-023-00914-7
pmc: PMC10484999
pii: 10.1038/s41408-023-00914-7