HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis.
AF4
ENL
HBO1
MLL
cancer biology
chromosomes
epigenetic regulators
gene expression
leukemia
mouse
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
25 08 2021
25 08 2021
Historique:
received:
17
12
2020
accepted:
12
08
2021
entrez:
25
8
2021
pubmed:
26
8
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.
Identifiants
pubmed: 34431785
doi: 10.7554/eLife.65872
pii: 65872
pmc: PMC8387021
doi:
pii:
Substances chimiques
KMT2A protein, human
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Histone Acetyltransferases
EC 2.3.1.48
KAT7 protein, human
EC 2.3.1.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021, Takahashi et al.
Déclaration de conflit d'intérêts
ST, AK, HO, RM, YK, TK, HM, TI, AT No competing interests declared, AY A.Y. received a research grant from Dainippon Sumitomo Pharma Co. Ltd.
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