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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

Eric Wang1, Jose Mario Bello Pineda2, Won Jun Kim3

  • 1The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.

Cancer Cell
|December 23, 2022
PubMed

Insights

Researchers identified RNA splicing factors that improve cancer therapy response. Targeting these factors, like RBM10, enhances venetoclax effectiveness in leukemia by disrupting key cell survival proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Therapy resistance is a significant obstacle in cancer treatment, particularly in acute myeloid leukemia (AML).
  • Identifying genetic factors that influence drug response is crucial for developing more effective cancer therapies.

Purpose of the Study:

  • To identify genomic determinants of drug response in acute myeloid leukemia (AML) using CRISPR-Cas9 screening.
  • To uncover novel therapeutic strategies for overcoming resistance to BCL2 inhibitors like venetoclax.

Main Methods:

  • CRISPR-Cas9 screening was employed across various AML therapies.
  • Functional genomics and molecular assays were used to investigate the role of RNA splicing factors.

Main Results:

  • Selective dependency on RNA splicing factors was identified, enhancing response to venetoclax.
  • Loss of RBM10 specifically increased venetoclax sensitivity in leukemia without affecting normal blood cells.
  • Combined inhibition of RBM10 and BCL2 led to XIAP inactivation and BCL2A1 downregulation, overcoming venetoclax resistance.

Conclusions:

  • RNA splicing plays a critical role in modulating cancer therapy response.
  • Targeting splicing factors, such as RBM10 or splicing kinases (CLKs, DYRKs), synergizes with venetoclax to improve AML treatment outcomes.
  • This study provides a promising strategy to enhance venetoclax-based therapies for AML.
Keywords:
BCL2CLKDYRKRBM10RNA splicingXIAPacute myeloid leukemiavenetoclax

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