Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms

• Published in: Cancer cell Vol. 33; no. 1; pp. 29 - 43.e7
• Main Authors: Kleppe, Maria, Koche, Richard, Zou, Lihua, van Galen, Peter, Hill, Corinne E., Dong, Lauren, De Groote, Sofie, Papalexi, Efthymia, Hanasoge Somasundara, Amritha V., Cordner, Keith, Keller, Matthew, Farnoud, Noushin, Medina, Juan, McGovern, Erin, Reyes, Jaime, Roberts, Justin, Witkin, Matthew, Rapaport, Franck, Teruya-Feldstein, Julie, Qi, Jun, Rampal, Raajit, Bernstein, Bradley E., Bradner, James E., Levine, Ross L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2018
• Subjects: Animals; chronic inflammation; Cytokines - metabolism; Gene Expression Regulation - drug effects; H3K27ac; Inflammation - drug therapy; Janus Kinase 2 - genetics; JQ1; Mice, Transgenic; Mutation - drug effects; Myeloproliferative Disorders - drug therapy; myeloproliferative neoplasms; Neoplasms - drug therapy; NF-kappa B - metabolism; NF-κB; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects; myeloproliferative neoplasms; NF-κB; JQ1; chronic inflammation; H3K27ac
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.11.009

Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-κB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo. [Display omitted] •Inflammation is associated with changes in the chromatin landscape of MPN cells•NF-κB is constitutively active in MPNs and drives MPN-associated inflammation•JQ1 shows potent anti-fibrotic efficacy in MPN mouse models•BET inhibition cooperates with JAK inhibition to ameliorate MPN-driven inflammation Kleppe et al. show that aberrant JAK2 signaling in myeloproliferative neoplasms (MPN) leads to chromatin changes that promote NF-κB signaling. BET inhibitors reduce NF-κB-induced inflammation and bone marrow fibrosis in MPN models, and combination treatment with BET and JAK inhibitors shows improved efficacy.