Open AccessAtypical activation of signaling downstream of inactivated Bcr‐Abl mediates chemoresistance in chronic myeloid leukemia
Author(s) -
Narasimhan Mythreyi,
Khamkar Vaishnavi,
Tilwani Sarika,
Dalal Sorab N.,
Shetty Dhanlaxmi,
Subramanian P.G.,
Gupta Sanjay,
Govekar Rukmini
Publication year - 2022
Publication title -
journal of cell communication and signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-021-00647-x
Subject(s) - imatinib , myeloid leukemia , cancer research , breakpoint cluster region , mapk/erk pathway , k562 cells , tyrosine kinase , leukemia , medicine , signal transduction , chemistry , immunology , biology , microbiology and biotechnology , receptor
Chronic myeloid leukemia (CML) epitomises successful targeted therapy, where inhibition of tyrosine kinase activity of oncoprotein Bcr‐Abl1 by imatinib, induces remission in 86% patients in initial chronic phase (CP). However, in acute phase of blast crisis, 80% patients show resistance, 40% among them despite inhibition of Bcr‐Abl1 activity. This implies activation of either Bcr‐Abl1‐ independent signalling pathways or restoration of signalling downstream of inactive Bcr‐Abl1. In the present study, mass spectrometry and subsequent in silico pathway analysis of differentiators in resistant CML‐CP cells identified key differentiators, 14–3‐3ε and p38 MAPK, which belong to Bcr‐Abl1 pathway. Their levels and activity respectively, indicated active Bcr‐Abl1 pathway in CML‐BC resistant cells, though Bcr‐Abl1 is inhibited by imatinib. Further, contribution of these components to resistance was demonstrated by inhibition of Bcr‐Abl1 down‐stream signalling by knocking‐out of 14–3‐3ε and inhibition of p38 MAPK activity. The observations merit clinical validation to explore their translational potential.