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Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells

Leukemia volume 26, pages 1407–1410 (2012)Cite this article

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders that arise from the transformation of hematopoietic stem cells. In 2005, several groups reported a single acquired point mutation in the Janus kinase 2 (Jak2) gene in the majority of patients with Philadelphia chromosome (Ph)-negative MPN.1 The mutation is believed to have a critical role in the pathogenesis of these disorders,2, 3 and it has been suggested that most patients harbor mutations (some of which remain to be identified) that potentially serve as a molecular target for selective Jak2 inhibition.4 Although small molecule Jak2 inhibitors are entering clinical trials, their ultimate efficacy is unclear.5 In addition to the concern of insufficient inhibition of mutated Jak2 in vivo or the emergence of resistance through activation of complementary pathways, many MPNs contain other mutational events (for example, mutation in exon12 of Mpl,6 or the KIT D618V mutation in patients with systemic mastocytosis7), and thus are not sensitive to Jak inhibitors. Therefore, the development of inhibitors to common mediators of diverse signaling pathways in this disease is very desirable.

One convergence point of these pathways is the transcription factor STAT5. STAT5 regulates the expression of genes controlling key events such as cell cycle progression and survival. Thus, continuous STAT5 activation drives increased expression of these genes that directly contribute to leukemogenesis. Continued STAT5 activation appears to be necessary for tumor cell survival,8 although normal cells are generally tolerant to the loss of STAT5 function. Consequently, STAT5 is an attractive target for cancer therapy. Increasing evidence indicates that STAT5 activation is required for Jak2 V617F-mediated transformation.9 As STAT5 is a critical mediator of the effects of Jak2 V617F, the development of drugs that inhibit this transcription factor holds promise as a treatment for MPN. Furthermore, the dual inhibition of both STAT5 and Jak2 may yield better disease control.

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Acknowledgements

This work was supported by the Kittredge Foundation (Dana-Farber Cancer Institute), the Brent Leahey Fund (Dana-Farber Cancer Institute), Gabrielle's Angel Foundation (New York, NY), the Claudia Adams Barr Program in Innovative Basic Cancer Research (Dana-Farber Cancer Institute) and Friends of the Dana-Farber Cancer Institute.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    M Bar-Natan, E A Nelson, S R Walker & D A Frank

  2. Departments of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA

    M Bar-Natan & D A Frank

  3. Translational Research Laboratory, The Center for Clinical and Translational Research, Dana-Farber Cancer Institute, Boston, MA, USA

    Y Kuang & R J Distel

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Correspondence to D A Frank.

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Bar-Natan, M., Nelson, E., Walker, S. et al. Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells. Leukemia 26, 1407–1410 (2012). https://doi.org/10.1038/leu.2011.338

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