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Publication

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

Cancer cell | 2018

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.

Pubmed ID: 29249691 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: R01 CA173636
Agency: NHLBI NIH HHS, United States
Id: K99 HL122503
Agency: NCI NIH HHS, United States
Id: P30 CA008748
Agency: NCI NIH HHS, United States
Id: R35 CA197594
Agency: NCI NIH HHS, United States
Id: R01 CA216421
Agency: NCI NIH HHS, United States
Id: K08 CA181507
Agency: NCI NIH HHS, United States
Id: R01 CA151949

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GraphPad Prism (tool)

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RRID:SCR_016052

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