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Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia

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Nicholas C. P. Cross, Yvette Hoade, William J. Tapper, Gonzalo Carreno-tarragona, Tiziana Fanelli, Mohamad Jawhar, Nicole Naumann, Iwo Pieniak, Johannes Lübke, Sahra Ali, Kaljit Bhuller, Sonja Burgstaller, Catherine Cargo, Jamie Cavenagh, Andrew S. Duncombe, Emma Das-gupta, Paul Evans, Peter Forsyth, Philip George, Charlotte Grimley & 16 more Fergus Jack, Laura Munro, Varun Mehra, Kavita Patel, Ali Rismani, Gabriela Sciuccati, Rowena Thomas-dewing, Patrick Thornton, Andres Virchis, Simon Watt, Louise Wallis, Alastair Whiteway, Kris Zegocki, Barbara J. Bain, Andreas Reiter, Andrew Chase

Original languageEnglish
JournalLeukemia
Early online date20 Dec 2018
DOIs
Publication statusPublished - 20 Dec 2018

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Abstract

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0–4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

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