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Paradigm shift: combination BET and JAK inhibition in myelofibrosis

Leukemia volume 35, pages 3361–3363 (2021)Cite this article

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Myelofibrosis (MF) is a clonal hematologic neoplasm that is characterized by myeloproliferation with bone marrow fibrosis, a pro-inflammatory state, aberrant hematopoietic stem cell (HSC) trafficking with extramedullary hematopoiesis, and potential for clonal evolution to acute myeloid leukemia (AML) [1]. Hyperactivity of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway due to acquisition of somatic driver mutations involving JAK2, CALR, and MPL is central to the pathogenesis of this myeloid malignancy [2]. In addition, constitutive activation of NF-kB in CD34+ MF cells is directly mediated by cell-autonomous downstream consequences of JAK-STAT signaling as well as non-cell-autonomous TNFα driven activation [3]. Aberrant activation of JAK-STAT and NF-kB target gene expression leads to the elaboration of a pathologic pro-inflammatory state that fuels the disease process. Recognition of this pathobiological feature led to the development and eventual approval of JAK inhibitors (JAKi; ruxolitinib, fedratinib) that are effective in addressing spleen and symptom burden, at the expense of worsening blood counts, but fail to meaningfully alter the natural course of disease for most patients [4, 5]. Despite the significant clinical benefit of JAKi, areas of unmet need remain present and include alleviation of anemia, effective therapy after JAKi failure, and ultimately a disease remission as a goal of therapy.

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Fig. 1: Inhibitors targeting Janus Associated Kinase 2 (JAK2) and bromodomain and extraterminal domain (BET) proteins cooperate to downregulate NFκB activity as well as expression of target genes that contribute to the underlying pathologic features of myelofibrosis.

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Acknowledgements

JM, AG, and SV conceived the work that led to the submission, drafted the paper, approved the final version, and agreed to be accountable for all aspects of the work.

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  1. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    John Mascarenhas

  2. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 44195, USA

    Aaron Gerds

  3. University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Srdan Verstovsek

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Correspondence to John Mascarenhas.

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JM has received research support paid to his institution from PharmaEssentia, Abbvie, CTI Bio, Merck, Roche, Novartis, BMS, Forbius, Kartos, Incyte, Geron, Sierra Oncology; consulting or advisory board fees from Kartos, CTI Bio, Constellation, Incyte, Roche, Novartis, BMS, Abbvie, PharmaEssentia, and Geron. AG has received advisory board fees from PharmaEssentia, BMS, Novartis, AbbVie, Sierra Oncology. SV has received research support paid to his institution from Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, Blueprint Medicines Corp., Novartis, Sierra Oncology, PharmaEssentia, Constellation, Protagonist, Kartos; advisory board fees from Constellation, BMS, Sierra Oncology, Incyte, Novartis, Celgene, PharmaEssentia.

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Mascarenhas, J., Gerds, A. & Verstovsek, S. Paradigm shift: combination BET and JAK inhibition in myelofibrosis. Leukemia 35, 3361–3363 (2021). https://doi.org/10.1038/s41375-021-01405-z

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