Laura Mazzera, Manuela Abeltino, Guerino Lombardi, Anna Maria Cantoni, Stefano Jottini, Attilio Corradi, Micaela Ricca, Elena Rossetti, Federico Armando, Angelo Peli, Anna Ferrari, Giovanni Martinelli, Maria Teresa Scupoli, Carlo Visco, Massimiliano Bonifacio, Alessia Ripamonti, Carlo Gambacorti-Passerini, Antonio Bonati, Roberto Perris, Paolo Lunghi
Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR's tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance...
June 29, 2023: Leukemia