title: PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia.
abstract: The DNA methyltransferases DNMT3A and DNMT3B are primarily responsible for de novo methylation of specific cytosine residues in CpG dinucleotides during mammalian development. While loss-of-function mutations in DNMT3A are highly recurrent in acute myeloid leukemia (AML), DNMT3A mutations are almost never found in AML patients with translocations that create oncogenic fusion genes such as PML-RARA, RUNX1-RUNX1T1, and MLL-AF9. Here, we explored how DNMT3A is involved in the function of these fusion genes. We used retroviral vectors to express PML-RARA, RUNX1-RUNX1T1, or MLL-AF9 in bone marrow cells derived from WT or DNMT3A-deficient mice. Additionally, we examined the phenotypes of hematopoietic cells from Ctsg-PML-RARA mice, which express PML-RARA in early hematopoietic progenitors and myeloid precursors, with or without DNMT3A. We determined that the methyltransferase activity of DNMT3A, but not DNMT3B, is required for aberrant PML-RARA-driven self-renewal ex vivo and that DNMT3A is dispensable for RUNX1-RUNX1T1- and MLL-AF9-driven self-renewal. Furthermore, both the PML-RARA-driven competitive transplantation advantage and development of acute promyelocytic leukemia (APL) required DNMT3A. Together, these findings suggest that PML-RARA requires DNMT3A to initiate APL in mice.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cole
authors.forename: Angela M
authors.initials: AM
authors.lastname: Verdoni
authors.forename: Shamika
authors.initials: S
authors.lastname: Ketkar
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Leight
authors.forename: David A
authors.initials: DA
authors.lastname: Russler-Germain
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Demeter
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C000715535:Dnmt3a protein, mouse; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; C493726:Runx1 protein, mouse; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A