Blood Journal
Leading the way in experimental and clinical research in hematology

Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

  1. Hanna L. M. Rajala1,
  2. Samuli Eldfors2,
  3. Heikki Kuusanmäki2,
  4. Arjan J. van Adrichem2,
  5. Thomas Olson3,
  6. Sonja Lagström2,
  7. Emma I. Andersson1,
  8. Andres Jerez4,
  9. Michael J. Clemente4,
  10. Yiyi Yan5,
  11. Dan Zhang3,
  12. Andy Awwad3,
  13. Pekka Ellonen2,
  14. Olli Kallioniemi2,
  15. Krister Wennerberg2,
  16. Kimmo Porkka1,
  17. Jaroslaw P. Maciejewski4,
  18. Thomas P. Loughran Jr.3,
  19. Caroline Heckman2, and
  20. Satu Mustjoki1,*
  1. 1 Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland;
  2. 2 Institute for Molecular Medicine Finland, Helsinki, Finland;
  3. 3 Penn State Hershey Cancer Institute, Pennsylvania State College of Medicine, Hershey, PA, United States;
  4. 4 The Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States;
  5. 5 York Hospital, Department of Medicine, York, PA, United States
  1. * Corresponding author; email: satu.mustjoki{at}

Key points

  • Somatic mutations were discovered for the first time in the SH2 domain of the STAT5b gene in large granular lymphocytic (LGL) leukemia

  • The mutations are activating and leading to increased phosphorylation and transcriptional activity of STAT5b


Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T-cells or NK-cells. Recently, somatic mutations in the STAT3 gene were discovered in 28-40% of LGL leukemia patients. By exome and transcriptome sequencing of two STAT3-mutation negative LGL leukemia patients we identified a recurrent, somatic missense mutation (Y665F) in the SH2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed two additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4/211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.

  • Submitted December 20, 2012.
  • Accepted April 7, 2013.