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<p>Tyrosine kinase inhibitors (TKIs) targeting the oncoprotein BCR-ABL have improved the prognosis for patients with chronic myeloid leukemia (CML). However, TKI resistance and persistent expression of BCR-ABL are responsible for the relapse and progression of CML. Here, we describe a novel approach to induce BCR-ABL protein degradation by small ubiquitin-like modifier (SUMO) modification. The E3 SUMO ligase TRIM28, upregulated during the progression of CML, promoted SUMOylation of BCR-ABL, thereby inhibiting its binding to the autophagy receptor P62 and repressing its autophagic degradation. Accordingly, genetic and pharmacological inhibition of TRIM28 or SUMOylation suppressed progression in both the CML mouse model and patient-derived xenograft model. Furthermore, targeting SUMOylation of BCR-ABL restrained the proliferation of TKI-resistant CML cells. These results identify the mechanism by which TRIM28 maintains BCR-ABL stability to promote CML progression and suggest SUMOylation as a target for CML treatment.</p><p></p>

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SUMOylation facilitates the stability of BCR-ABL to promote chronic myeloid leukemia progression

  • 期刊论文

  • 发表日期：

    2025年3月27日

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  • Lu Zhang,
  • Xuefeng Wang,
  • Dongmei Hu,
  • Shijie Li,
  • Mingshan Sun,
  • Qian Liu,
  • Huimin Feng,
  • Minran Zhou,
  • Chunyan Chen,
  • Huan Zhou,
  • Sai Ma

摘要

Tyrosine kinase inhibitors (TKIs) targeting the oncoprotein BCR-ABL have improved the prognosis for patients with chronic myeloid leukemia (CML). However, TKI resistance and persistent expression of BCR-ABL are responsible for the relapse and progression of CML. Here, we describe a novel approach to induce BCR-ABL protein degradation by small ubiquitin-like modifier (SUMO) modification. The E3 SUMO ligase TRIM28, upregulated during the progression of CML, promoted SUMOylation of BCR-ABL, thereby inhibiting its binding to the autophagy receptor P62 and repressing its autophagic degradation. Accordingly, genetic and pharmacological inhibition of TRIM28 or SUMOylation suppressed progression in both the CML mouse model and patient-derived xenograft model. Furthermore, targeting SUMOylation of BCR-ABL restrained the proliferation of TKI-resistant CML cells. These results identify the mechanism by which TRIM28 maintains BCR-ABL stability to promote CML progression and suggest SUMOylation as a target for CML treatment.