Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm.
Animals
Cell Proliferation
/ genetics
Chromosomes, Human, Pair 6
/ genetics
Chromosomes, Human, Pair 8
/ genetics
Core Binding Factor Alpha 1 Subunit
/ genetics
DNA-Binding Proteins
/ genetics
Dendritic Cells
/ pathology
Dioxygenases
Enhancer Elements, Genetic
/ genetics
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Jurkat Cells
Leukemia, Myeloid, Acute
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms, Experimental
/ genetics
Promoter Regions, Genetic
/ genetics
Proto-Oncogene Proteins
/ genetics
Proto-Oncogene Proteins c-myc
/ genetics
Translocation, Genetic
/ genetics
Whole-Body Irradiation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 04 2019
10 04 2019
Historique:
received:
17
04
2018
accepted:
26
03
2019
entrez:
12
4
2019
pubmed:
12
4
2019
medline:
30
4
2019
Statut:
epublish
Résumé
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.
Identifiants
pubmed: 30971697
doi: 10.1038/s41467-019-09710-z
pii: 10.1038/s41467-019-09710-z
pmc: PMC6458132
doi:
Substances chimiques
Core Binding Factor Alpha 1 Subunit
0
DNA-Binding Proteins
0
MYC protein, human
0
Proto-Oncogene Proteins
0
Proto-Oncogene Proteins c-myc
0
RUNX2 protein, human
0
Dioxygenases
EC 1.13.11.-
Tet2 protein, mouse
EC 1.13.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1653Commentaires et corrections
Type : ErratumIn
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