Abstract
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 Eμ-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.
Keywords:
Apoptosis inhibitors; Cancer; Hematology; Therapeutics; Transcription.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Alternative Splicing / drug effects*
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Disease Models, Animal
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Drug Screening Assays, Antitumor
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Epoxy Compounds / pharmacology*
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Epoxy Compounds / therapeutic use
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Female
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Macrolides / pharmacology*
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Macrolides / therapeutic use
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Male
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Mice
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Mice, Transgenic
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Middle Aged
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Mitochondria / drug effects
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Mitochondria / pathology
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Mutation
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Phosphoproteins / genetics
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Primary Cell Culture
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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RNA Splicing Factors / genetics
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Spliceosomes / drug effects
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Spliceosomes / metabolism
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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Thiophenes / pharmacology
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Thiophenes / therapeutic use
Substances
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BCL2 protein, human
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Bridged Bicyclo Compounds, Heterocyclic
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E 7107
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Epoxy Compounds
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MCL1 protein, human
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Macrolides
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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RNA Splicing Factors
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S63845
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SF3B1 protein, human
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Sulfonamides
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TCL1A protein, human
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Thiophenes
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venetoclax