(HealthDay News) – Approximately 40% of patients with T-cell large granular lymphocytic leukemia have mutations in the Src homology 2 (SH2) dimerization and activation domain of the signal transducer and activator of the transcription 3 (STAT3) gene, according to a study published in the May 17 issue of the New England Journal of Medicine.
Hanna L.M. Koskela, MD, of the University of Helsinki and Helsinki University Central Hospital, and colleagues used exome sequencing techniques to sequence somatic mutations in cytotoxic T lymphocytes obtained from 76 patients with T-cell large granular lymphocytic leukemia.
The researchers found that 40% of patients with T-cell large granular lymphocytic leukemia exhibited mutations in the STAT3 gene. Four recurrent mutational hot spots were identified, all of which were located in exon 21, encoding the SH2 domain. The resulting amino acid alterations led to a more hydrophobic protein surface and correlated with STAT3 phosphorylation and localization in the nucleus. In affected patients, there was an upregulation of downstream targets of the STAT3 pathway. Neutropenia and rheumatoid arthritis were more commonly found in patients with STAT3 mutations.
“In conclusion, STAT3 is frequently mutated in large granular lymphocytic leukemia, highlighting key steps in the molecular pathogenesis of this rare disease,” the authors write. “Structural and functional data suggest that the observed mutations result in STAT3 hyperactivation and may confer ligand-independent signaling.”
Several authors disclosed financial relationships with pharmaceutical and diagnostic technology companies.