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

Seda Baykal-Köse; Eda Acikgoz; Ahmet Sinan Yavuz; Öykü Gönül Geyik; Halil Ateş; Osman Uğur Sezerman; Güner Hayri Özsan; Zeynep Yüce

doi:10.1371/journal.pone.0229104

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

PLoS One. 2020 Feb 27;15(2):e0229104. doi: 10.1371/journal.pone.0229104. eCollection 2020.

Authors

Seda Baykal-Köse¹, Eda Acikgoz^{2

3}, Ahmet Sinan Yavuz⁴, Öykü Gönül Geyik¹, Halil Ateş⁵, Osman Uğur Sezerman⁶, Güner Hayri Özsan⁵, Zeynep Yüce¹

Affiliations

¹ Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
² Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
³ Department of Histology and Embryology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey.
⁴ Department of Molecular Biology, Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
⁵ Department of Hematology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
⁶ Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem University, Istanbul, Turkey.

Abstract

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 β-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Cadherins / genetics
Cadherins / metabolism
Cell Proliferation / drug effects
Cell Proliferation / genetics
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics
Fusion Proteins, bcr-abl / antagonists & inhibitors
Fusion Proteins, bcr-abl / genetics*
Fusion Proteins, bcr-abl / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Imatinib Mesylate / pharmacology
Imatinib Mesylate / therapeutic use
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Mice
Mutation / drug effects
Oligonucleotide Array Sequence Analysis
Protein Domains / genetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use

Substances

Antigens, CD
CDH1 protein, human
Cadherins
Protein Kinase Inhibitors
abl-bcr fusion protein, human
Imatinib Mesylate
Fusion Proteins, bcr-abl

Associated data

figshare/10.6084/m9.figshare.c.4787100.v1

Grants and funding

Dokuz Eylul University Scientific Research Projects, grants no:2012KBSAG092 and 2009KBSAG029. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.