Somatic Mutations in STAT3 Drive Large Granular Lymphocytic Leukemia

Large granular lymphocytic leukemia is a rare lymphoproliferative disease characterized by clonal expansion of CD8⁺ cytotoxic T lymphocytes. Because many cases are indolent and mimic or are accompanied by autoimmune processes, such as rheumatoid arthritis and cytopenias, diagnosis can be difficult, and the underlying genetic defects remain unknown. To identify potential somatic driver mutations, Koskela and colleagues performed whole-exome sequencing of leukemic cells from an index patient with untreated T-cell large granular lymphocytic leukemia and found a heterozygous missense mutation in signal transducer and activator of transcription 3 (STAT3), an oncogene implicated in many types of cancer. Targeted sequencing in 76 study patients with large granular lymphocytic leukemia identified 5 additional missense mutations and 1 insertion mutation in STAT3, establishing a mutation frequency of 40%. Importantly, all 7 mutations were located within the SH2 domain that mediates STAT3 dimerization and activation and were predicted to increase the hydrophobicity of the dimerization surface and therefore the stability of the active protein. In support of this hypothesis, the authors found activation of STAT3 and upregulation of STAT3 transcriptional targets in patient samples and enhanced transcriptional activity of STAT3 mutants in vitro. Clinical correlation showed that rheumatoid arthritis and neutropenia were more common in patients with STAT3 mutation. Together, these findings establish aberrant STAT3 activation and downstream signaling as a cause of large granular lymphocytic leukemia and suggest that STAT3 mutation status may aid in the diagnosis and/or characterization of this rare disease.

Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012;366:1905–13.

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