Genetic basis for iMCD-TAFRO Journal Article


Authors: Yoshimi, A.; Trippett, T. M.; Zhang, N.; Chen, X.; Penson, A. V.; Arcila, M. E.; Pichardo, J.; Baik, J.; Sigler, A.; Harada, H.; Fajgenbaum, D. C.; Dogan, A.; Abdel-Wahab, O.; Xiao, W.
Article Title: Genetic basis for iMCD-TAFRO
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 MEK2P128L mutation and a germline RUNX1G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2P128L 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 RUNX1G60C 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. © 2020, Springer Nature Limited.
Keywords: mitogen activated protein kinase; adult; child; clinical article; controlled study; human tissue; preschool child; young adult; human cell; somatic mutation; pathogenesis; fluorouracil; genetic analysis; enzyme inhibition; mitogen activated protein kinase kinase 2; thrombocytopenia; kidney failure; enzyme activation; wild type; fever; syndrome; hematopoietic stem cell; histiocytosis; transcription factor runx1; germline mutation; cell self-renewal; mitogen activated protein kinase kinase inhibitor; interleukin 3; angiofollicular lymph node hyperplasia; anasarca; mapk signaling; human; male; female; priority journal; article; runx1 gene; tafro syndrome; solid malignant neoplasm; mek2 gene
Journal Title: Oncogene
Volume: 39
Issue: 15
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2020-04-09
Start Page: 3218
End Page: 3225
Language: English
DOI: 10.1038/s41388-020-1204-9
PUBMED: 32051554
PROVIDER: scopus
PMCID: PMC7148173
DOI/URL:
Notes: Article -- Export Date: 1 May 2020 -- Source: Scopus
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MSK Authors
  1. Tanya M Trippett
    110 Trippett
  2. Maria Eugenia Arcila
    459 Arcila
  3. Ahmet Dogan
    230 Dogan
  4. Alexander Vincent Penson
    31 Penson
  5. Akihide   Yoshimi
    31 Yoshimi
  6. Wenbin Xiao
    31 Xiao
  7. Jee Yeon Baik
    17 Baik
  8. Allison Marie Sigler
    9 Sigler