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.
Original language | English |
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Article number | 101521 |
Journal | Cell Reports Medicine |
Volume | 5 |
Issue number | 5 |
Number of pages | 24 |
ISSN | 2666-3791 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Publisher Copyright:
© 2024 The Authors
- BCR::ABL1-independent resistance, CML, CRISPR-Cas9 screening, drug combination, drug repurposing, drug screening, KCTD5, progenitor, stem cell, TKI
Research areas
ID: 396938349