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Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in

Mengdan Liu1,2,3, Ming Yan1,2, Amanda G Davis1,2

  • 1Moores Cancer Center, University of California San Diego, La Jolla, CA.

Blood Neoplasia
|July 30, 2025
PubMed

Insights

Histone H3-associated protein (HASPIN) kinase is a novel therapeutic target for acute myeloid leukemia (AML). Targeting HASPIN with CHR-6494 and venetoclax shows synergistic effects and overcomes drug resistance in AML.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acute myeloid leukemia (AML) presents challenges due to drug resistance, relapse, and poor survival rates.
  • Combination therapies are effective but limited by target availability and rational pairing strategies.
  • Identifying novel dependencies in AML is crucial for developing new treatments.

Purpose of the Study:

  • To identify novel therapeutic targets in AML using a kinase-focused CRISPR screen.
  • To investigate the role of HASPIN kinase in AML pathogenesis and splicing regulation.
  • To evaluate the efficacy of a HASPIN inhibitor, CHR-6494, alone and in combination with venetoclax for AML treatment.

Main Methods:

  • A human kinase domain-targeted CRISPR screen was employed to identify AML dependencies.
  • Proteomics data mining was used to characterize HASPIN kinase substrates, particularly SR proteins.
  • The effects of HASPIN depletion and CHR-6494 treatment on AML cell viability, cell cycle, and splicing were assessed.
  • Combination therapy with CHR-6494 and venetoclax was evaluated in AML cell models, including venetoclax-resistant lines.

Main Results:

  • HASPIN kinase was identified as a significant dependency in AML, with its depletion impairing growth and altering transcription.
  • HASPIN was characterized as a splicing regulatory kinase, and its inhibition dysregulated splicing in AML cells.
  • CHR-6494 demonstrated efficacy in reducing AML cell viability across subtypes while sparing healthy cells.
  • The combination of CHR-6494 and venetoclax exhibited synergistic effects, reducing AML cell viability and overcoming venetoclax resistance.

Conclusions:

  • HASPIN kinase represents a novel therapeutic target for AML.
  • HASPIN plays an underappreciated role in splicing regulation within AML.
  • A combination therapy of CHR-6494 and venetoclax offers a promising strategy for clinical testing in AML, including resistant cases.

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