A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML
Bo-Rui Chen, Anagha Deshpande, 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 J. Eaves, Irmela Jeremias, Torsten Haferlach, David A. Frank, Ze’ev A. Ronai, Sumit K. Chanda, Scott A. Armstrong, Peter D. Adams, Ross L. Levine, Aniruddha J. Deshpande, Aniruddha J. Deshpande
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.