STAT5b in LGL leukemia – a novel therapeutic target?

The activation of signal transducer and activator of transcription (STAT) family genes, especially STAT5 and STAT3, has been established in multiple solid tumors and hematological malignancies. Recently we discovered somatic activating STAT3 mutations in 40% of T-cell large granular lymphocytic (LGL) leukemia and 30% of NK-cell LGL leukemia patients (Koskela, Eldfors et al. NEJM, 2012, 17;366(20):1905-13 and Jerez et al. Blood, 2012, 120(15):3048-57). Interestingly, our current findings indicate that also activating STAT5b mutations can be found in LGL leukemia patients (Rajala et al. Blood Apr 17, 2013). LGL leukemia is incurable disease, characterized by chronic expansion of cytotoxic T or NK cells, and it often manifests with other hematological and autoimmune disorders such as rheumatoid arthritis. Autoimmune mediated cytopenias such as neutropenia are common and can be life-threatening due to increased infectionsusceptibility. Leukemic T-LGLs have a phenotype of terminally differentiated effector-memory cells and, accordingly, the role of viral antigens or autoantigens as potential drivers of the clonal expansion has been speculated. However, in leukemic LGL cells the normal activation-induced cell death (AICD) is impaired, and several cell-survival signaling pathways such as JAKSTAT, MAPK/ERK/Ras, PI3K-AKT, and NfκB are activated. Common immunosuppressive agents such as prednisone and methotrexate are current first-line treatments, and no targeted therapies exist. By means of whole exome sequencing we identified a STAT5b mutation Y665F in two STAT3 mutationnegative LGL leukemia patients, and in the following screening of a large patient cohort (n>200) another STAT5b mutation N642H in two additional patients. Both these mutations are located in the src-like homologue 2 (SH2) domain of STAT5b. No mutations were found