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Atypical activation of signaling downstream of inactivated Bcr-Abl mediates chemoresistance in chronic myeloid leukemia

Abstract

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.

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Data availability

SWATH and iTRAQ data used in the current study have been deposited to the Proteome Xchange Consortium via the PRIDE (Vizcaíno et al. 2016) partner repository. SWATH dataset identifier is PXD009686 while identifier for iTRAQ is PXD025173 (Username—reviewer_pxd025173@ebi.ac.uk; Password—AQQpqd0I).

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Acknowledgements

We acknowledge the support of Mr. Shashi Dolas and Mrs. Savita Chavan from mass spectrometry facility—ACTREC, Dr. Ajit Datar, Mr. Shailendra Rane and Mr. Ashutosh Shelkar from Shimadzu analytical private limited, Mumbai. We also thank Dr. Dr. Tadashi Nagai, Jichi Medical University, Tochigi, Japan for providing wild type (drug sensitive) K562, KCL22 and KU812 cell lines.

Funding

This work was funded by Intramural Research Grant of Tata Memorial Centre.

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Conceptualization, RG; methodology, MN, VK, ST, SD, DS, PG and SG; formal analysis, MN; investigation, MN; resources, RG; data curation, RG; writing—original draft preparation, MN; writing—review and editing, RG; visualization, RG; supervision, RG; project administration, RG; funding acquisition, RG All authors have read and agreed to the published version of the manuscript.

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Correspondence to Rukmini Govekar.

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Narasimhan, M., Khamkar, V., Tilwani, S. et al. Atypical activation of signaling downstream of inactivated Bcr-Abl mediates chemoresistance in chronic myeloid leukemia. J. Cell Commun. Signal. 16, 207–222 (2022). https://doi.org/10.1007/s12079-021-00647-x

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Keywords

  • Chronic myeloid leukemia
  • Bcr-Abl1
  • Imatinib resistance
  • Proteomics
  • Mass spectrometry
  • p38-MAPK