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ACUTE LYMPHOBLASTIC LEUKEMIA

Heat stress targets and degrades BCR::ABL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia

Leukemia volume 39, pages 2140–2151 (2025)Cite this article

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Abstract

BCR::ABL1 oncofusion protein drives Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL), making it a critical therapeutic target. Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have revolutionized the treatment of Ph+ ALL patients. However, mutations in the kinase domain of BCR::ABL1 commonly impair the sensitivity to TKIs, resulting in drug resistance and poor prognosis in Ph+ ALL. Here we report that heat stress selectively destabilizes BCR::ABL1 and its common drug-resistant mutants without affecting the native BCR and ABL proteins through inducing liquid-to-solid phase transition. Mechanistic studies revealed that heat stress facilitated recruitment of BCR::ABL1 signaling components (e.g., SHIP2, Sts1, PI3K-p85α and Shc) in a kinase activity dependent manner and stimulated BCR::ABL1 oligomerization through its coiled-coil domain, resulting in formation of a large, thermally unstable signaling complex. This process triggers non-canonical K27-linked ubiquitination mediated by c-Cbl E3 ubiquitin ligase, ultimately leading to BCR::ABL1 degradation via the ubiquitin-proteasome pathway. Functionally, heat stress effectively suppressed proliferation of BCR::ABL1-driven leukemia cells, including drug resistant mutants in vitro and decreased tumor burden in vivo. Our findings established that thermal-based therapy as a novel strategy to selectively target and degrade both unmutated and drug-resistant BCR::ABL1 oncoproteins, offering a promising adjuvant approach to overcome TKI resistance in Ph+ ALL.

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Fig. 1: Heat stress reduces BCR::ABL1 solubility and leads to protein aggregation.
Fig. 2: Heat stress facilitates recruitment of signaling components to BCR::ABL1.
Fig. 3: Heat stress induced oligomerization of BCR::ABL1 leads to formation of high molecular weight complex.
Fig. 4: Heat stress degrades BCR::ABL1 through the proteasome pathway via c-Cbl mediated K27 ubiquitination.
Fig. 5: Continuous heat stress inhibits Ph + ALL cell proliferation in vitro and modulates leukemia progression in vivo.
Fig. 6: Continuous heat treatment overcomes Ph + ALL in TKI-resistant in vivo model.

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Data availability

The raw sequence data have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA011771) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human. All other data reported in this paper will be shared by the lead contact upon request.

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Acknowledgements

This manuscript was funded by National Natural Science Foundation of China (No. 82170143, 82370191, 82200160; 31970706).

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Author notes

  1. These authors contributed equally: Chang Yang, Yuan-Yuan Kang, Chen-Ying Zhu.

Authors and Affiliations

  1. Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China

    Chang Yang, Yuan-Yuan Kang, Chen-Ying Zhu, Pei-Han Yu, Tao Yang, Yong-Qin Liu, Ze-Yan Zhang & Hua Naranmandura

  2. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China

    Yuan-Yuan Kang, Pei-Han Yu, Tao Yang & Hua Naranmandura

  3. Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yafang Ma

  4. Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan

    Noriyuki Suzuki

  5. Department of Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    Yasumitsu Ogra

  6. Centre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, China

    Mikael Björklund

  7. University of Edinburgh Medical School, Biomedical Sciences, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, UK

    Mikael Björklund

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Contributions

Conception: CY, MB, HN; Data curation: CY, YYK, CYZ, YQL, ZYZ; Methodology: CY, YYK, CYZ, YFM, PHY, YO, NS; Resources: CY, YFM, YO, NS, HN; Investigation: CY, YYK, CYZ, PHY, TY, MB, HN; Visualization: YYK, CYZ, TY, YQL, ZYZ; Funding acquisition: CY, MB, HN; Project administration: CY, MB, HN; Supervision: MB, HN; Writing–original draft: CY, YYK, CYZ, MB, HN; Writing–review and editing: CY, YYK, CYZ, YO, NS, MB, HN.

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Correspondence to Mikael Björklund or Hua Naranmandura.

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Yang, C., Kang, YY., Zhu, CY. et al. Heat stress targets and degrades BCR::ABL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 39, 2140–2151 (2025). https://doi.org/10.1038/s41375-025-02709-0

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