DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding
Menée à partir d'échantillons de moelle osseuse prélevés sur 18 patients atteints d'une leucémie promyélocytaire aiguë et à l'aide de modèles murins, cette étude montre que des anomalies de la méthylation de l'ADN interviennent de façon tardive dans l'évolution de la maladie
The origin of aberrant DNA methylation in cancer remains largely unknown. In this study, we elucidated the DNA methylome in primary Acute Promyelocytic Leukemia (APL) and the role of PML-RARα in establishing these patterns. APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes and remission bone marrow. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score and Flt3-mutation status characterized methylation subtypes. Transcription factor binding sites, e.g. c-myc binding sites were associated with low methylation. SUZ12 and REST binding sites identified in embryonic stem cells were, however, preferentially DNA hypermethylated in APL. Unexpectedly, PML-RARα binding sites were also protected from aberrant DNA methylation in APL. In line, myeloid cells from pre-leukemic PML-RARα knock-in mice did not show altered DNA methylation and expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. ATRA treatment of APL blasts did also not result in immediate DNA methylation changes. These results suggest that aberrant DNA methylation is associated with leukemia phenotype but not required for PML-RARα–mediated initiation of leukemogenesis.