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Genetic basis for iMCD-TAFRO.
- Source :
-
Oncogene [Oncogene] 2020 Apr; Vol. 39 (15), pp. 3218-3225. Date of Electronic Publication: 2020 Feb 12. - Publication Year :
- 2020
-
Abstract
- 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 <superscript>P128L</superscript> mutation and a germline RUNX1 <superscript>G60C</superscript> mutation in two patients with iMCD-TAFRO, respectively. The MEK2 <superscript>P128L</superscript> 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 <superscript>G60C</superscript> mutation abolished the transcriptional activity of wild-type RUNX1 and functioned as a dominant negative form of RUNX1, resulting in enhanced self-renewal activity in hematopoietic stem/progenitor cells. Interestingly, ERK was heavily activated in both patients, highlighting a potential role for activation of MAPK signaling in iMCD-TAFRO pathogenesis and a rationale for exploring inhibition of the MAPK pathway as a therapy for iMCD-TAFRO. Moreover, these data suggest that iMCD-TAFRO might share pathogenetic features with clonal inflammatory disorders bearing MEK and RUNX1 mutations such as histiocytoses and myeloid neoplasms.
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 32051554
- Full Text :
- https://doi.org/10.1038/s41388-020-1204-9