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Chen, B.R.* ; Deshpande, A.* ; Barbosa, K.O.* ; Kleppe, M.* ; Lei, X.* ; Yeddula, N.* ; Sánchez Vela, P.* ; Campos, A.R.* ; Wechsler-Reya, R.J.* ; Bagchi, A.* ; Meshinchi, S.* ; Eaves, C.J.* ; Jeremias, I. ; Haferlach, T.* ; Frank, D.A.* ; Ronai, Z.A.* ; Chanda, S.* ; Armstrong, S.A.* ; Adams, P.* ; Levine, R.L.*

A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis In AF10-rearranged AML.

Blood 137, 3403-3415 (2021)
Publ. Version/Full Text Postprint DOI
Open Access Green
Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of AML driven by the most common AF10 fusion proteins, 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 anti-oncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Jak Inhibitors; Calm-af10; Fusion; Translocation; Atovaquone; Subgroups; T(10/11); Calm; Mll
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 137, Issue: 24, Pages: 3403-3415 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Grants Leukemia & Lymphoma Society
Rally Foundation for Childhood Cancer Research
Luke Tatsu Johnson Foundation
Children's Cancer Research Fund
V Foundation for Cancer Research (TVF)
Lady Tata Foundation
Memorial Sloan Kettering Cancer Center (MSKCC) from the NIH National Cancer Institute
NIH National Cancer Institute grant
Specialized Center of Research (SCOR) grants from the Leukemia & Lymphoma Society
NIH National Cancer Institute
National Institutes of Health (NIH) National Cancer Institute