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.
Highlights
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disease, clinically characterized by an increase in myeloid lineage cells at all stages of differentiation
In the aim to identify underlying resistance mechanisms in K562-IR cells, we initially investigated the presence of ABL domain mutations (S1 Materials and Methods of S1 Table)
The success of Tyrosine kinase inhibitor (TKI) in the treatment of CML lies in triggering cell death by blocking BCR-Abl signaling
Summary
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disease, clinically characterized by an increase in myeloid lineage cells at all stages of differentiation. The Philadelphia chromosome (derivative 22) derived from the t(9;22)(q34;q11) translocation, is the hallmark of the disease, transforming the hematopoietic stem cell (HSC) in to a leukemic stem cell (LSC) that gives rise to the disease. The translocation results in the fusion of the proto-oncogene ABL located on the long arm of chromosome 9, with the BCR gene on chromosome 22. Adaptive phenotypic shift is a drug resistance mechanism in CML cells
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