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

Publication date: Available online 14 December 2017
Source:Cancer Cell
Author(s): Maria Kleppe, Richard Koche, Lihua Zou, Peter van Galen, Corinne E. Hill, Lauren Dong, Sofie De Groote, Efthymia Papalexi, Amritha V. Hanasoge Somasundara, Keith Cordner, Matthew Keller, Noushin Farnoud, Juan Medina, Erin McGovern, Jaime Reyes, Justin Roberts, Matthew Witkins, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E. Bernstein, James E. Bradner, Ross L. Levine
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.

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Teaser

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.


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