Genetic 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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
Oncogene - 39(2020), 15 vom: 13. Apr., Seite 3218-3225 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yoshimi, Akihide [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.12.2020 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41388-020-1204-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM306458438 |
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| 100 | 1 | |a Yoshimi, Akihide |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genetic basis for iMCD-TAFRO |
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| 520 | |a 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 | ||
| 650 | 4 | |a Case Reports | |
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| 700 | 1 | |a Trippett, Tanya M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xueyan |e verfasserin |4 aut | |
| 700 | 1 | |a Penson, Alexander V |e verfasserin |4 aut | |
| 700 | 1 | |a Arcila, Maria E |e verfasserin |4 aut | |
| 700 | 1 | |a Pichardo, Janine |e verfasserin |4 aut | |
| 700 | 1 | |a Baik, Jeeyeon |e verfasserin |4 aut | |
| 700 | 1 | |a Sigler, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Harada, Hironori |e verfasserin |4 aut | |
| 700 | 1 | |a Fajgenbaum, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Dogan, Ahmet |e verfasserin |4 aut | |
| 700 | 1 | |a Abdel-Wahab, Omar |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Wenbin |e verfasserin |4 aut | |
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