Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms
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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.
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Bromodomain inhibitors combined with JAK2 inhibition markedly reduce serum levels of inflammatory cytokines.
“as reported for bromodomain inhibitors, which, when combined with JAK2 inhibition, markedly reduce the serum levels of inflammatory cytokines51.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [51]
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Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
Klampfl, T., Gisslinger, H., Harutyunyan, A. S., Nivarthi, H., Rumi, E., Milosevic, J. D., Them, N. C. C., Berg, T., Gisslinger, B., Pietra, D., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1311347 · Cited by 2,003 · see citing works
Somatic <i>CALR</i> Mutations in Myeloproliferative Neoplasms with Nonmutated <i>JAK2</i>
Nangalia, J., Massie, C. E., Baxter, E. J., Nice, F. L., Gundem, G., Wedge, D. C., Avezov, E., Li, J., Kollmann, K., Kent, D. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1312542 · Cited by 1,756 · see citing works
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BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure
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“reduce serum levels of inflammatory cytokines, accompanied by reduction in disease burden, and reversal of bone marrow fibrosis in preclinical models (Kleppe et al., 2018).”
BackgroundThe BET family in immunity and disease
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- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Corresponding author
- Bradner, James E.
- Levine, Ross L.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 33
- Issue
- 1
- Pages
- 29-43.e7
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5760343
- OpenAlex
- W2773899764
- Cited by
- 279
- References
- 9
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 31 · 2023: 38 · 2022: 32 · 2021: 64 · 2020: 41 · 2019: 23 · 2018: 12
- FWCI
- 11.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-04-09)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (R01CA151949, CA173636, R35197594, K99 HL122503-01A1)
- Janus Project
- LLS SCOR
- Starr Cancer Consortium
- MSKCC (P30 CA008748)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- myeloproliferative neoplasms, JAK/STAT signaling, NF-κB signaling, BET proteins, enhancer regulation, myelofibrosis, inflammatory cytokines, bone marrow fibrosis
- MeSH terms
- Animals, Gene Expression Regulation, Inflammation, Mice, Transgenic, Mutation, Myeloproliferative Disorders, Neoplasms, Signal Transduction, Cytokines, NF-kappa B, Protein Kinase Inhibitors, Janus Kinase 2
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