A JAK/STAT-MEDIATED INFLAMMATORY SIGNALING CASCADE DRIVES ONCOGENESIS IN AF10-REARRANGED AML.

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

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