DNA methylation : a new actor in CML biology

DNA methylation : a new actor in CML biology

Chronic myeloid leukemia (CML), a cancer of the white blood cell, results from a translocation event that ultimately leads to the production of BCR-ABL1, a chimeric oncoprotein that promotes CML by aberrantly phosphorylating target proteins. Nonetheless, this event on its own, cannot account for an increasing number of clinical observation suggesting the involvement of other pathways, among which DNA methylation alteration emerges as a relevant candidate.

On that basis the teams of Marc BERGER (CHU, Clermont-Ferrand) and Philippe ARNAUD have characterized  for the first  time the DNA methylation patterns of CML cell subsets (immature and mature cells) isolated form the same clone during the early stage of the disease, before any treatment    (Maupetit-Méhouas, Court, Bourgne et al.,). Altogether, this collaborative study demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations paved the way for new therapeutic strategies based on epigenetic drugs.

DNA methylation defects have emerged as an attractive candidate to account for intra-clonal heterogeneity and in vivo persistence of chronic myeloid leukemia (CML) sub-clone(s). Nonetheless, it is not known to which extent subpopulations of cells at the early stage of CML are aberrantly methylated and how this defect contributes to transcriptional alteration genome-wide.

To address these issues, the teams of Marc BERGER (CHU, Clermont-Ferrand) and Philippe ARNAUD have characterized the DNA methylation patterns of chronic phase CML cell subsets (immature and mature cells) before any treatment and compared them to those of similar cell subsets from healthy donors.

For the first time, they show that widespread DNA methylation abnormalities exist at early CML stages (chronic phase of the disease) and that they can affect the transcriptional landscape in several manners. Indeed, the characterization of DNA methylation alterations in leukemia stem cells-enriched CD34+CD15- population indicates the presence of early alterations in DNA methylation specific to this immature subpopulation. The finding that several genes the expression of which might be affected by these DNA methylation changes are implicated in the survival or proliferation of CML progenitors suggests that these alterations could contribute to the development of CML or of resistance to therapies (particularly tyrosine kinase inhibitors) in sub-clones. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in chronic phase -CML cells.  Besides providing a resource to decipher the molecular bases of in vivo persistence of CML sub-clones our study also supports that the combination of epigenetic drugs and tyrosine kinase inhibitors could be relevant for the treatment of chronic phase CML.

This study has been published in Molecular Oncology.

Last modified: 11/12/2018