STAT3 Y640F

STAT3 activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, STAT3 activating mutations may play a role in disease pathogenesis in a subset of RA patients.

STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.

First line single agent therapy with methotrexate (MTX), cyclosporine, and cyclophosphamide have shown similar overall response rates of 40-50%, though STAT3 mutated disease is associated with better response to MTX...Our patient was initiated on prednisone, though due to poor tolerance was transitioned to MTX titrated to 12...The same study found better responses to cyclosporine as first line therapy, an interesting observation as MTX has been generally accepted as first line therapy based on predominantly retrospective studies, though these studies did not stratify treatment responses by TCR phenotype. These findings underscore the need for prospective studies characterizing Tγδ specific disease course, survival analyses and treatment response.

The initial dose of cyclophosphamide and prednisone were 100mg/day and 0.5-1mg/kg/day, respectively...The complete response rate (CRR) [31% (5/16) vs 33% (19/58), P=0.909] and overall response rate (ORR) [56% (9/16) vs 50% (29/58), P=0.658] of cyclosporine (CsA) treatment were similar in patients with STAT3 mutations or not...Leukemia. 2020, 34: 1116–1124.