Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells

Baykal-Kose S., Açıkgöz E., Yavuz A. S., Geyik O. G., Ate H., SEZERMAN O. U., ...More

PLOS ONE, vol.15, no.2, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 15 Issue: 2
  • Publication Date: 2020
  • Doi Number: 10.1371/journal.pone.0229104
  • Journal Name: PLOS ONE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, Index Islamicus, Linguistic Bibliography, MEDLINE, Pollution Abstracts, Psycinfo, zbMATH, Directory of Open Access Journals
  • Van Yüzüncü Yıl University Affiliated: Yes


Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and beta-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/ organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.