A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML Journal Article

   

Authors:	Chen, B. R.; Deshpande, A.; Barbosa, K.; Kleppe, M.; Lei, X.; Yeddula, N.; Sánchez Vela, P.; Campos, A. R.; Wechsler-Reya, R. J.; Bagchi, A.; Meshinchi, S.; Eaves, C.; Jeremias, I.; Haferlach, T.; Frank, D. A.; Ronai, Z.; Chanda, S.; Armstrong, S. A.; Adams, P. D.; Levine, R. L.; Deshpande, A. J.
Article Title:	A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML
Abstract:	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. © 2021 by The American Society of Hematology.
Journal Title:	Blood
Volume:	137
Issue:	24
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2021-06-17
Start Page:	3403
End Page:	3415
Language:	English
DOI:	10.1182/blood.2020009023
PUBMED:	33690798
PROVIDER:	scopus
PMCID:	PMC8212510
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108583209&doi=10.1182%2fblood.2020009023&partnerID=40&md5=f55a8f6eb88fbcb39bf6936c3d8645c6
Notes:	Article -- Export Date: 1 July 2021 -- Source: Scopus

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