A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
04
09
2020
accepted:
11
02
2021
pubmed:
11
3
2021
medline:
15
12
2021
entrez:
10
3
2021
Statut:
ppublish
Résumé
Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
Identifiants
pubmed: 33690798
pii: S0006-4971(21)00578-4
doi: 10.1182/blood.2020009023
pmc: PMC8212510
doi:
Substances chimiques
MLLT10 protein, human
0
Neoplasm Proteins
0
STAT Transcription Factors
0
Transcription Factors
0
Janus Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3403-3415Subventions
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197594
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA176745
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA154880
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200643
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204639
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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