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Updated: Jan 7, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Published on: January 7, 2019

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USP8-EIF2S1 signaling enhances CML cell survival under TKI-induced stress

Chethampadi Gopi Mohan1, Keechilat Pavithran2

  • 1Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.

The FEBS Journal
|December 26, 2025
PubMed

Insights

USP8 deubiquitinase stabilizes eIF2α, sustaining the unfolded protein response (UPR) and mediating tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). Targeting this USP8-eIF2α axis may overcome TKI resistance in CML patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chronic myeloid leukemia (CML) is driven by the BCR-ABL fusion kinase.
  • Resistance to tyrosine kinase inhibitors (TKIs) is a major clinical obstacle in CML treatment.

Purpose of the Study:

  • To identify novel mechanisms underlying TKI resistance in CML.
  • To investigate the role of USP8 in mediating CML cell survival under TKI treatment.

Main Methods:

  • The study utilized molecular biology techniques to analyze the function of USP8 in CML cells.
  • Investigated the interaction between USP8, EIF2S1, and the unfolded protein response (UPR) pathway.

Main Results:

  • USP8 was identified as a key mediator of TKI resistance.
  • USP8 deubiquitinates and stabilizes EIF2S1 (eIF2α) by removing K48-linked ubiquitin chains.
  • Stabilization of EIF2S1 sustains PERK-EIF2S1-mediated UPR signaling, promoting CML cell survival.

Conclusions:

  • The USP8-EIF2S1 axis is crucial for CML cell adaptation and survival during TKI therapy.
  • Targeting the USP8-EIF2S1 pathway presents a potential therapeutic strategy to overcome TKI resistance in CML.
Keywords:
TKI resistance drugsUPR signalingchronic myeloid leukemiadeubiquitinating enzymestructure‐based drug designubiquitin‐specific protease family

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