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Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia

Kibeom Park1, Hee-Seop Yoo2,3, Chang-Kyu Oh4,5

  • 1School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

Cancer Medicine
|March 30, 2022
PubMed

Insights

Cobbl1 protein drives blast crisis progression and drug resistance in chronic myeloid leukemia (CML). It disrupts apoptosis by binding PACSIN2, which normally inhibits pathways causing resistance.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Chronic myeloid leukemia (CML) blast crisis (BC) is characterized by disease progression and resistance to tyrosine kinase inhibitors (TKIs).
  • The molecular mechanisms underlying TKI resistance and BC progression in CML remain incompletely understood.
  • Cobbl1 has been implicated in BC progression and TKI resistance, but its specific role and interacting partners are not fully elucidated.

Purpose of the Study:

  • To investigate the molecular mechanism by which Cobbl1 contributes to TKI resistance and BC progression in CML.
  • To identify novel Cobbl1-interacting proteins and elucidate their role in regulating apoptosis and drug resistance.
  • To explore the potential clinical relevance of the Cobbl1/PACSIN2/SH3BP1 pathway in CML patient progression.

Main Methods:

  • Co-immunoprecipitation assays to identify Cobbl1 binding partners.
  • Western blotting and apoptosis assays in K562 cells to assess TKI-induced apoptosis.
  • Rac1 activation assays and pathway analysis.
  • Analysis of Cobbl1, PACSIN2, and SH3BP1 expression in CML patient samples at different disease phases.

Main Results:

  • PACSIN2, a novel Cobbl1 binding protein, promotes TKI-induced apoptosis in K562 cells.
  • Cobbl1 suppresses TKI-induced apoptosis by binding PACSIN2, thereby inhibiting its pro-apoptotic function.
  • Cobbl1 also binds and inhibits SH3BP1, which activates the Rac1 pathway, leading to TKI resistance.
  • Clinical analysis revealed elevated Cobbl1 and SH3BP1 expression in BC-phase CML patients, correlating with disease severity.

Conclusions:

  • The Cobbl1/PACSIN2/SH3BP1 pathway is a critical regulator of TKI resistance and BC progression in CML.
  • Cobbl1 promotes CML progression and drug resistance by disrupting PACSIN2-mediated apoptosis and activating the SH3BP1/Rac1 pathway.
  • Targeting this pathway may offer a novel therapeutic strategy for overcoming TKI resistance in CML.
Keywords:
Cobll1PACSIN2SH3BP1blastic transformationchronic myeloid leukemia

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