Reduced levels of ITGB1 cause activation of p38MAPK-ERK-LYN axis of BCR::ABL1 signaling despite inactivation of the oncoprotein by imatinib – novel resistance mechanism in blast crisis of chronic myeloid leukemia unraveled

作者：Neha Agrawal, Mythreyi Narasimhan, Rahul Mojidra, Bhausaheb Bagal, Navin Khattry, Anant Gokarn, Sachin Punattar, Rukmini Govekar · 发表于：Cell Communication and Signaling · 年份：2026 · DOI：10.1186/s12964-026-02893-1 · 研究领域：Chronic Myeloid Leukemia Treatments、Cell Adhesion Molecules Research、Acute Myeloid Leukemia Research

Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signa...