Integrated drug profiling and CRISPR screening identify BCR::ABL1-independent vulnerabilities in chronic myeloid leukemia
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BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34+ leukemic stem/progenitor cells using 100 single drugs and TKI-drug combinations and identify sensitivities to Wee1, MDM2, and BCL2 inhibitors. These agents effectively inhibit primitive CD34+CD38− CML cells and demonstrate potent synergies when combined with TKIs. Flow-cytometry-based drug screening identifies mepacrine to induce differentiation of CD34+CD38− cells. We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.
Originalsprog | Engelsk |
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Artikelnummer | 101521 |
Tidsskrift | Cell Reports Medicine |
Vol/bind | 5 |
Udgave nummer | 5 |
Antal sider | 24 |
ISSN | 2666-3791 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This work was supported by the Academy of Finland (grant nos. 292605 , 287224 , 310507 , 313267 , and 326238 ); a Finnish special governmental subsidy for health sciences, research, and training; the Signe and Ane Gyllenberg Foundation ; the Finnish Cancer Institute ; the Nordic Cancer Union ; the Helsinki Institute of Life Science ; Cancer Foundation Finland ; the Relander Foundation ; the EUTOS project for CML 2022; a Pfizer investigator initiated research grant; the European Union\u2019s Horizon Europe Research & Innovation Programme (REMEDi4ALL project, grant agreement no. 101057442 ); the Cancer Society of Finland ; and the Sigrid Jus\u00E9lius Foundation . The FIMM-HTB unit is supported by the University of Helsinki , HiLIFE , and Biocenter Finland .
Publisher Copyright:
© 2024 The Authors
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