| First Author | Kleppe M | Year | 2018 |
| Journal | Cancer Cell | Volume | 33 |
| Issue | 1 | Pages | 29-43.e7 |
| PubMed ID | 29249691 | Mgi Jnum | J:253743 |
| Mgi Id | MGI:6110625 | Doi | 10.1016/j.ccell.2017.11.009 |
| Citation | Kleppe M, et al. (2018) Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 33(1):29-43.e7 |
| abstractText | 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 kappaB (NF-kappaB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-kappaB 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. |
