Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms Journal Article
| Authors: | Kleppe, M.; Koche, R.; Zou, L.; van Galen, P.; Hill, C. E.; Dong, L.; De Groote, S.; Papalexi, E.; Hanasoge Somasundara, A. V.; Cordner, K.; Keller, M.; Farnoud, N.; Medina, J.; McGovern, E.; Reyes, J.; Roberts, J.; Witkin, M.; Rapaport, F.; Teruya-Feldstein, J.; Qi, J.; Rampal, R.; Bernstein, B. E.; Bradner, J. E.; Levine, R. L. |
| Article Title: | 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. 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. © 2017 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; myelofibrosis; human cell; janus kinase 2; janus kinase inhibitor; drug efficacy; monotherapy; nonhuman; drug targeting; mouse; allele; animal tissue; cd34 antigen; animal experiment; animal model; inflammation; immunoglobulin enhancer binding protein; in vivo study; enzyme activation; stem cell; oncogene; gene activation; cytokine; transactivation; gene control; cytokine production; gamma interferon inducible protein 10; chronic inflammation; myeloproliferative neoplasm; rna sequence; blood level; enhancer region; nf-κb; myeloproliferative neoplasms; epithelial derived neutrophil activating factor 78; ruxolitinib; disease burden; human; male; female; priority journal; article; bromodomain inhibitor; jq1; 4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 a][1,4]diazepine 6 acetic acid tert butyl ester; h3k27ac; jak-stat signaling |
| Journal Title: | Cancer Cell |
| Volume: | 33 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-01-08 |
| Start Page: | 29 |
| End Page: | 43.e7 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2017.11.009 |
| PUBMED: | 29249691 |
| PROVIDER: | scopus |
| PMCID: | PMC5760343 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
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