Qingfei Jiang, Catriona Jamieson  Cancer Cell 

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BET’ing on Dual JAK/BET Inhibition as a Therapeutic Strategy for Myeloproliferative Neoplasms  Qingfei Jiang, Catriona Jamieson  Cancer Cell  Volume 33, Issue 1, Pages 3-5 (January 2018) DOI: 10.1016/j.ccell.2017.12.007 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Combination Therapy Targeting JAK/STAT and BET Signaling Reduces Disease Burden of MPN Constitutive activation of JAK/STAT in MPN cells drives alterations in H3K6me1 (poised enhancers) and H3K27ac (active enhancers) chromatin state, which leads to NF-κB activation and increased chronic inflammation signals. Specifically, the occupancy of H3K27ac at the Nfkb1 gene loci leads to increased expression of NF-κB and enrichment of NF-κB pathway transcripts, indicating crosstalk between epigenetic and transcriptional regulatory network in MF cells. The collaboration between JAK/STAT and NF-κB pathways activated by inflammatory stimuli also feed into aberrant cytokine production and MF progression. The BET family of acetylated (Ac) lysine readers further augments the pro-inflammatory signals. A combination treatment of JAK/STAT inhibitor (Ruxolitinib) and BET inhibitor (JQ1) synergistically blocks NF-κB hyperactivation and inflammatory cytokine production, which attenuates disease burden and eliminates bone marrow fibrosis in two mouse models of MPN (MPLW515L and JAK2V617F). Cancer Cell 2018 33, 3-5DOI: (10.1016/j.ccell.2017.12.007) Copyright © 2017 Elsevier Inc. Terms and Conditions