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1.
Turk J Haematol ; 40(2): 101-117, 2023 05 29.
Article in English | MEDLINE | ID: mdl-37026766

ABSTRACT

Objective: Chronic myeloid leukemia (CML) is a disease caused by the acquisition of BCR-ABL1 fusion in hematopoietic stem cells. In this study, we focus on the oncofetal ENOX2 protein as a potential secretable biomarker in CML. Materials and Methods: We used cell culture, western blot, quantitative RT-PCR, ELISA, transcriptome analyses, and bioinformatics techniques to investigate ENOX2 mRNA and protein expression. Results: Western blot analyses of UT-7 and TET-inducible Ba/F3 cell lines demonstrated the upregulation of the ENOX2 protein. BCR-ABL1 was found to induce ENOX2 overexpression in a kinase-dependent manner. We confirmed increased ENOX2 mRNA expression in a cohort of CML patients at diagnosis. In a series of CML patients, ELISA assays showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML compared to controls. Reanalyzing the transcriptomic dataset confirmed ENOX2 mRNA overexpression in the chronic phase of the disease. Bioinformatic analyses identified several genes whose mRNA expressions were positively correlated with ENOX2 in the context of BCR-ABL1. Some of them encode proteins involved in cellular functions compatible with the growth deregulation observed in CML. Conclusion: Our results highlight the upregulation of a secreted redox protein in a BCR-ABL1-dependent manner in CML. The data presented here suggest that ENOX2, through its transcriptional mechanism, plays a significant role in BCR-ABL1 leukemogenesis.


Subject(s)
Fusion Proteins, bcr-abl , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Multienzyme Complexes/metabolism , Oxidation-Reduction , Protein Kinase Inhibitors
2.
PLoS One ; 15(2): e0229104, 2020.
Article in English | MEDLINE | ID: mdl-32106243

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 ß-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.


Subject(s)
Drug Resistance, Neoplasm/genetics , Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Neoplastic/drug effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/pharmacology , 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 , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , Gene Expression Profiling , Humans , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mice , Mutation/drug effects , Oligonucleotide Array Sequence Analysis , Protein Domains/genetics , Protein Kinase Inhibitors/therapeutic use
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