Open AccessGenetic basis for iMCD-TAFRO
Author(s) -
Akihide Yoshimi,
Tanya M. Trippett,
Nan Zhang,
Xueyan Chen,
A. Penson,
Maria E. Arcila,
Janine Pichardo,
Jeeyeon Baik,
Allison Sigler,
Hironori Harada,
David C Fajgenbaum,
Ahmet Doğan,
Omar AbdelWahab,
Wenbin Xiao
Publication year - 2020
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-020-1204-9
Subject(s) - cancer research , germline mutation , biology , pathogenesis , cytokine , mapk/erk pathway , mutation , organomegaly , haematopoiesis , anasarca , immunology , signal transduction , medicine , stem cell , disease , microbiology and biotechnology , genetics , gene , biochemistry
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 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.