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

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.