STAT5B Mutations in Myeloid Neoplasms Differ by Disease Subtypes but Characterize a Subset of Chronic Myeloid Neoplasms With Eosinophilia and/or Basophilia

Authors

C Cameron Yin
Wayne Tam
Serena M Walker
Amandeep Kaur
Madhu M Ouseph
Wei Xie
Olga K Weinberg
Peng Li
Zhuang Zuo
Mark J Routbort
Simon Chen
L Jeffrey Medeiros
Tracy I George
Attilio Orazi
Daniel A Arber
Adam Bagg
Robert P Hasserjian
Sa A Wang

Publication Date

6-1-2024

Journal

Haematologica

Abstract

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.

Keywords

Humans, STAT5 Transcription Factor, Mutation, Eosinophilia, Male, Female, Middle Aged, Aged, Basophils, Adult, Myeloproliferative Disorders, Aged, 80 and over, High-Throughput Nucleotide Sequencing, Myelodysplastic Syndromes

Comments

Associated Data

PMID: 37981812