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

Abstract

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.

• Authors: 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 Witkin, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E Bernstein, James E Bradner, Ross L Levine
• Journal: Cancer cell (Cancer Cell) Vol. 33 Issue 1 Pg. 29-43.e7 (01 08 2018) ISSN: 1878-3686 [Electronic] United States
• PMID: 29249691 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• NF-kappa B
• Protein Kinase Inhibitors
• Janus Kinase 2

Topics

• Animals
• Cytokines (metabolism)
• Gene Expression Regulation (drug effects)
• Inflammation (drug therapy)
• Janus Kinase 2 (genetics)
• Mice, Transgenic
• Mutation (drug effects)
• Myeloproliferative Disorders (drug therapy)
• NF-kappa B (metabolism)
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)