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 |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work