Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2025年7月22日

查看全文
  • Chang Yang,
  • Yuan-Yuan Kang,
  • Chen-Ying Zhu,
  • Yafang Ma,
  • Pei-Han Yu,
  • Tao Yang,
  • Yong-Qin Liu,
  • Ze-Yan Zhang,
  • Noriyuki Suzuki,
  • Yasumitsu Ogra,
  • Mikael Björklund,
  • Hua Naranmandura

摘要

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.