title: DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding.
abstract: The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. 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 (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Schoofs
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.forename: Katja
authors.initials: K
authors.lastname: Hebestreit
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.forename: Isabell
authors.initials: I
authors.lastname: Schulze
authors.forename: Mads
authors.initials: M
authors.lastname: Lerdrup
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Dietrich
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.forename: Anika
authors.initials: A
authors.lastname: Witten
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Eva
authors.initials: E
authors.lastname: Lengfelder
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Peter
authors.initials: P
authors.lastname: Schlenke
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002877:Chromosomes, Human / Q000648:ultrastructure; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011289:Preleukemia / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D063151:Polycomb Repressive Complex 2; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000099229:RE1-Silencing Transcription Factor; C430461:SUZ12 protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein