DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34 CD15 cells in early chronic-phase chronic myeloid leukemia.
Fiche publication
Date publication
mars 2018
Journal
Molecular oncology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUERCI-BRESLER Agnès
Tous les auteurs :
Maupetit-Mehouas S, Court F, Bourgne C, Guerci-Bresler A, Cony-Makhoul P, Johnson H, Etienne G, Rousselot P, Guyotat D, Janel A, Hermet E, Saugues S, Berger J, Arnaud P, Berger MG
Lien Pubmed
Résumé
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 heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP-CML CD34 CD15 (immature) and CD34 CD15 (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34 CD15 and CD34 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 and CD34 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 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 of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP-CML.
Mots clés
CML , DNA methylation, epigenetics, leukemic stem cells, transcriptional defects
Référence
Mol Oncol. 2018 Mar 25;: