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Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors

journal contribution
submitted on 2023-10-17, 08:18 and posted on 2023-10-17, 12:23 authored by Mohamed A. Ismail, Gheyath K. Nasrallah, Maria Monne, Ali AlSayab, Mohamed A. Yassin, Govindarajulu Varadharaj, Salma Younes, Claudio Sorio, Richard Cook, Helmout Modjtahedi, Nader I. Al-Dewik

Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in BCR-ABL1 are well studied but fail to explain 20–40% of resistant cases, suggesting the activation of alternative, BCR-ABL1-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and remained at low level in resistant patients. In this study, we aimed to identify genetic variants in PTPRG that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-non-responsive. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+14412delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that PTPRG variants may act as an indirect resistance mechanism of BCR-ABL1 to affect TKI treatment.

Other Information

Published in: Gene
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.gene.2021.146101

Funding

Open Access funding provided by the Qatar National Library

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License

Institution affiliated with

  • Hamad Medical Corporation
  • Interim Translational Research Institute - HMC
  • National Center for Cancer Care and Research - HMC
  • Women's Wellness and Research Center - HMC
  • Hamad General Hospital - HMC
  • Qatar University
  • Qatar University Health - QU
  • College of Health Sciences - QU HEALTH
  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU