Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia

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

doi:10.1038/s41375-018-0342-3

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.

Highlights

Eosinophilia, defined as an elevation of the peripheral blood (PB) eosinophil count above 0.5 × 109/L, is conventionally divided into three main categories: primary, secondary and idiopathic
We previously described RNA-seq analysis to search for cryptic fusion genes in 14 patients with MPN-eo or idiopathic hypereosinophilia with a normal karyotype [6]
STAT5 is encoded by two different genes, STAT5A and STAT5B, located closely together at chromosome 17q11.2 that encode proteins with >90% amino acid identity and largely redundant functions

Summary

Introduction

Eosinophilia, defined as an elevation of the peripheral blood (PB) eosinophil count above 0.5 × 109/L, is conventionally divided into three main categories: primary, secondary (reactive) and idiopathic. Primary eosinophilia is a clonal hematologic disorder in which the eosinophils form part of the neoplastic clone. Non-clonal eosinophilia may be driven by a wide range of underlying conditions including allergic disorders, autoimmunity, infectious diseases, lymphoproliferative disorders, solid tumours, drug

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Conclusion