期刊
JCI INSIGHT
卷 3, 期 19, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.121438
关键词
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资金
- NIH/National Cancer Institute (NIH/NCI) [P01 CA206978]
- NIH/NCI CLL Research Consortium Grant [P01-CA081534]
- NIH/NCI [R01 CA216273, U10 CA180861]
The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an E mu-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.
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