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

Bo Rui Chen, Anagha Deshpande, Karina Barbosa, Maria Kleppe, Xue Lei, Narayana Yeddula, Pablo Sánchez Vela, Alexandre Rosa Campos, Robert J. Wechsler-Reya, Anindya Bagchi, Soheil Meshinchi, Connie Eaves, Irmela Jeremias, Torsten Haferlach, David A. Frank, Ze'ev Ronai, Sumit Chanda, Scott A. Armstrong, Peter D. Adams, Ross L. LevineAniruddha J. Deshpande

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish
Pages (from-to)3403-3415
Number of pages13
Issue number24
StatePublished - 17 Jun 2021
Externally publishedYes


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