DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34 + CD15 − cells in early chronic-phase chronic myeloid leukemia

Abstract : Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating intraclonal heterogeneity in chronic-phase CML (CP-CML). To determine the basis of this heterogene-ity, we conducted the first exhaustive characterization of the DNA methyla-tion pattern of sorted CP-CML CD34 + CD15 À (immature) and CD34 À CD15 + (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34 + CD15 À and CD34 À CD15 + cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP-CML and HD samples, with only a subset of them in common between CD34 + CD15 À and CD34 À CD15 + cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP-CML cells, among which 18 and 81, respectively, were in CP-CML CD34 + CD15 À cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP-CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape
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Molecular Oncology, Elsevier, 2018, 12 (6), pp.814 - 829. 〈10.1002/1878-0261.12191〉
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Soumis le : vendredi 9 novembre 2018 - 12:05:31
Dernière modification le : jeudi 29 novembre 2018 - 01:22:01

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Stéphanie Maupetit-Méhouas, Franck Court, Céline Bourgne, Agnès Guerci-Bresler, Pascale Cony-Makhoul, et al.. DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34 + CD15 − cells in early chronic-phase chronic myeloid leukemia. Molecular Oncology, Elsevier, 2018, 12 (6), pp.814 - 829. 〈10.1002/1878-0261.12191〉. 〈hal-01917284〉

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