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JCI Insight. 2018 Oct 4;3(19). pii: 121438. doi: 10.1172/jci.insight.121438. [Epub ahead of print]

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
4
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
5
H3 Biomedicine Inc., Cambridge, Massachusetts, USA.
6
Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
7
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8
Harvard Medical School, Boston, Massachusetts, USA.
9
Broad Institute, Cambridge, Massachusetts, USA.
10
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
11
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
12
Department of Biomolecular Engineering, University of California, Santa Cruz, California, USA.

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

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