biostudies-literatureYoshimi AMEXT | Japan Society for the Promotion of ScienceCastleman Awareness and Research Effort/Castleman Disease Collaborative NetworkStarr FoundationLauri Strauss Leukemia FoundationNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstitutePershing Square FoundationNCI NIH HHSEdward P. Evans FoundationLeukemia and Lymphoma Society3218-3225https://www.ebi.ac.uk/biostudies/studies/S-EPMC7148173biostudies-literatureUnknown39(15)TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2^P128L mutation and a germline RUNX1^G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2^P128L mutation, which has been identified previously in solid tumor and histiocytosis patients, caused hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity and sensitized the cells to various MEK inhibitors. The RUNX1^G60C mutation aboliOncogeneGenetic basis for iMCD-TAFRO.PMC7148173I8-A8-075P30 CA008748R01 HL128239Trippett TMDogan ABaik JZhang NFajgenbaum DCXiao WPenson AVHarada HArcila MEYoshimi APichardo JChen XSigler AAbdel-Wahab OfalseGenetic basis for iMCD-TAFRO.TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2^P128L mutation and a germline RUNX1^G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2^P128L mutation, which has been identified previously in solid tumor and histiocytosis patients, caused hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity and sensitized the cells to various MEK inhibitors. The RUNX1^G60C mutation aboli2020-01-01T00:00:00Z2020 Apr2026-05-01T01:00:55.321Z2020-08-15T07:09:17ZS-EPMC71481733205155410.1038/s41388-020-1204-9