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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
09:02

Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation

Published on: November 26, 2018

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

Elisa Ten Hacken1, Rebecca Valentin1, Fara Faye D Regis1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

JCI Insight
|October 5, 2018
PubMed

Insights

Aberrant splicing drives therapeutic resistance in chronic lymphocytic leukemia (CLL). Modulating splicing with E7107 reprograms cancer cell dependencies, sensitizing CLL to venetoclax, offering hope for resistant cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Therapeutic resistance in cancer, particularly chronic lymphocytic leukemia (CLL), presents a significant clinical challenge.
  • Identifying novel vulnerabilities is crucial for developing effective treatment strategies against resistant cancer types.

Purpose of the Study:

  • To investigate the role of aberrant splicing in CLL and its association with therapeutic sensitivity.
  • To evaluate the efficacy of spliceosome modulation in overcoming resistance to BCL2 inhibitors like venetoclax in CLL.

Main Methods:

  • Analysis of aberrant splicing patterns in chronic lymphocytic leukemia (CLL) cells.
  • Treatment of human and murine CLL cells with the spliceosome modulator E7107.
  • Assessment of changes in apoptotic pathway dependencies (MCL1, BCL2) and drug sensitivity.

Main Results:

  • Pervasive aberrant splicing was identified as a hallmark of CLL, independent of splicing factor mutation status.
  • Splicing modulation with E7107 altered CLL cell survival pathways, decreasing MCL1 dependence and increasing BCL2 dependence.
  • Combined treatment with E7107 and venetoclax sensitized primary human CLL and venetoclax-resistant murine CLL models.

Conclusions:

  • Aberrant splicing is a key feature in CLL that can be targeted therapeutically.
  • Spliceosome modulators can reprogram apoptotic dependencies, overcoming resistance to BCL2 inhibitors.
  • Combination therapy with venetoclax and splicing modulators shows preclinical promise for treating resistant CLL.
Keywords:
Apoptosis inhibitorsCancerHematologyTherapeuticsTranscription

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