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Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib.

ABSTRACT: In this study, we determined the gene expression profiles of bone marrow-derived cell fractions, obtained from normal subjects and Chronic Myeloid Leukemia (CML) patients, that were highly enriched for hematopoietic stem (HSCs) and progenitor (HPCs) cells. Our results indicate that the profiles of CML HSCs and HPCs were closer to that of normal progenitors, whereas normal HSCs showed the most different expression profile of all. We found that the expression profiles of HSCs and HPCs from CML marrow were closer to each other than those of HSCs and HPCs from normal marrow. The major biologic processes dysregulated in CML cells included DNA repair, cell cycle, chromosome condensation, cell adhesion, and the immune response. We also determined the genomic changes in both normal and CML progenitor cells under culture conditions, and found that several genes involved in cell cycle, steroid biosynthesis, and chromosome segregation were upregulated, whereas genes involved in transcription regulation and apoptosis were downregulated. Interestingly, these changes were the same, regardless of the addition of Imatinib (IM) to the culture. Finally, we identified three genes-PIEZO2, RXFP1, and MAMDC2- that are preferentially expressed by CML primitive cells and that encode for cell membrane proteins; thus, they could be used as biomarkers for CML stem cells.

SUBMITTER: Aviles-Vazquez S

PROVIDER: S-EPMC5727298 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib.

Avilés-Vázquez Sócrates S Chávez-González Antonieta A Hidalgo-Miranda Alfredo A Moreno-Lorenzana Dafne D Arriaga-Pizano Lourdes L Sandoval-Esquivel Miguel Á MÁ Ayala-Sánchez Manuel M Aguilar Rafael R Alfaro-Ruiz Luis L Mayani Hector H

Cancer medicine 20171013 12

In this study, we determined the gene expression profiles of bone marrow-derived cell fractions, obtained from normal subjects and Chronic Myeloid Leukemia (CML) patients, that were highly enriched for hematopoietic stem (HSCs) and progenitor (HPCs) cells. Our results indicate that the profiles of CML HSCs and HPCs were closer to that of normal progenitors, whereas normal HSCs showed the most different expression profile of all. We found that the expression profiles of HSCs and HPCs from CML mar ...[more]

PMID: 29030909

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Project description:BACKGROUND:The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses in 40-60% of patients, an occurrence very likely due to the persistence of leukemic stem cells that are scarcely sensitive to TKi. Nevertheless, TKi are still the only current treatment option for CML patients. OBJECTIVE:The aim of this study was to compare the effects of TKi belonging to different generations, imatinib and ponatinib (first and third generation, respectively), on progenitor/stem cell expansion potential and markers. PATIENTS AND METHODS:We used stabilized CML cell lines (KCL22, K562 and LAMA-84 cells), taking advantage of the previous demonstration of ours that cell lines contain cell subsets endowed with progenitor/stem cell properties. Primary cells explanted from CML patients were also used. The effects of TKi on the expression of stem cell related genes were compared by quantitative PCR. Flow cytometry was performed to evaluate aldehyde-dehydrogenase (ALDH) activity and the expression of cluster of differentiation (CD) cell surface hematopoietic stem cell markers. Progenitor/stem cell potential was estimated by serial colony formation ability (CFA) assay. RESULTS:Ponatinib was more effective than imatinib for the reduction of cells with ALDH activity and progenitor/stem cell potential of CML patient-derived cells and cell lines. Furthermore, ponatinib was more effective than imatinib in reducing the percentage of CD26-expressing cells in primary CML cells, whereas imatinib and ponatinib showed similar efficacy on KCL22 cells. Both drugs strongly upregulated NANOG and SOX2 in CML cell lines, but in KCL22 cells this upregulation was significantly lower with ponatinib than with imatinib, an outcome compatible with a lower level of enrichment of the stem cell compartment upon ponatinib treatment. CONCLUSION:Ponatinib seems to target CML progenitor/stem cells better than imatinib.

Dataset Information

Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib.

Publications

Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib.

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