Genetic basis for iMCD-TAFRO

Authors

Akihide Yoshimi, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Tanya M. Trippett, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Nan Zhang, Rochester Regional HealthFollow
Xueyan Chen, Department of Laboratory Medicine, University of Washington, Seattle, WA, 98109, USA.
Alexander V. Penson, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Maria E. Arcila, Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Janine Pichardo, Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Jeeyeon Baik, Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Allison Sigler, Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Hironori Harada, Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
David C. Fajgenbaum, Castleman Disease Collaborative Network, Philadelphia, PA, USA.
Ahmet Dogan, Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Omar Abdel-Wahab, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Wenbin Xiao, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Department

Pathology

Document Type

Article

Publication Title

Oncogene

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 mutation and a germline RUNX1 mutation in two patients with iMCD-TAFRO, respectively. The MEK2 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 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.

First Page

3218

Last Page

3225

DOI

10.1038/s41388-020-1204-9

Volume

39

Issue

15

Publication Date

4-1-2020

Medical Subject Headings

Adult; Castleman Disease (genetics, pathology); Child, Preschool; Core Binding Factor Alpha 2 Subunit (genetics); DNA Mutational Analysis; Humans; Lymph Nodes (pathology); MAP Kinase Kinase 2 (genetics); MAP Kinase Signaling System (genetics); Male; Young Adult

PubMed ID

32051554

Recommended Citation

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. (2020). Genetic basis for iMCD-TAFRO. Oncogene, 39 (15), 3218-3225. https://doi.org/10.1038/s41388-020-1204-9