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

STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

  1. Andres Jerez1,
  2. Michael J. Clemente1,
  3. Hideki Makishima1,
  4. Hanna Koskela2,
  5. Francis LeBlanc3,
  6. Kwok Peng Ng1,
  7. Thomas Olson3,
  8. Bartlomiej Przychodzen1,
  9. Manuel Afable1,
  10. Ines Gomez-Segui1,
  11. Kathryn Guinta1,
  12. Lisa Durkin4,
  13. Eric D. Hsi4,
  14. Kathy McGraw5,
  15. Dan Zhang3,
  16. Marcin W. Wlodarski6,
  17. Kimmo Porkka2,
  18. Mikkael A. Sekeres1,
  19. Alan List5,
  20. Satu Mustjoki2,
  21. Thomas P. Loughran3, and
  22. Jaroslaw P. Maciejewski1
  1. 1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  2. 2Hematology Research Unit, Department of Medicine, Division of Hematology, Helsinki University Central Hospital, Helsinki, Finland;
  3. 3Penn State Hershey Cancer Institute, Penn State Hershey College of Medicine, Hershey, PA;
  4. 4Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH;
  5. 5H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and
  6. 6Department of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany


Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.

  • Submitted June 5, 2012.
  • Accepted July 12, 2012.
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