<i>STAT5B</i> mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia
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
Affiliations
C. Cameron Yin
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
Wayne Tam
Division of Hematopathology, Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, Greenvale, NY
Serena M. Walker
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Amandeep Kaur
Department of Pathology, University of Chicago, Chicago, IL
Madhu M. Ouseph
Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York, NY
Wei Xie
Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR
Olga K.Weinberg
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
Peng Li
Department of Pathology, University of Utah, Salt Lake City, UT
Zhuang Zuo
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
Mark J. Routbort
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
Simon Chen
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
L. Jeffrey Medeiros
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
Tracy I George
Department of Pathology, University of Utah, Salt Lake City, UT
Attilio Orazi
Department of Pathology, Texas Tech University, El Paso, TX
Daniel A. Arber
Department of Pathology, University of Chicago, Chicago, IL
Adam Bagg
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Robert P. Hasserjian
Department of Pathology, Massachusetts General Hospital, Boston, MA
Sa A. Wang
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
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.
