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Genetic basis for iMCD-TAFRO

Oncogene volume 39, pages 3218–3225 (2020)Cite this article

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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.

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Fig. 1: Clinical presentation and genetic features of patients with iMCD-TAFRO.
Fig. 2: Pathogenic roles of mutant MEK2 and mutant RUNX1.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Sequencing data have been deposited in NCBI ClinVar under accession number SCV000965590-SCV000965596. Other data that support this study’s findings are available from the authors upon reasonable request.

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Acknowledgements

This study was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. AY is a Special Fellow of The Leukemia and Lymphoma Society and supported by grants from the Aplastic Anemia and MDS International Foundation (AA&MDSIF), the Lauri Strauss Leukemia Foundation, the Leukemia and Lymphoma Society Special Fellow Award, and JSPS Overseas Research Fellowships. OA-W is supported by grants from NIH/NHLBI (R01 HL128239), the Department of Defense Bone Marrow Failure Research Program (W81XWH-16-1-0059), the Starr Foundation (I8-A8-075), the Henry & Marilyn Taub Foundation, the Edward P. Evans Foundation, the Josie Robertson Investigator Program, the Leukemia and Lymphoma Society, and the Pershing Square Sohn Cancer Research Alliance. WX is supported by a grant from Castleman’s Awareness and Research Effort/Castleman Disease Collaborative Network.

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Author notes

  1. Nan Zhang

    Present address: Department of Pathology, Rochester General Hospital, Rochester, NY, 14621, USA

  2. These authors contributed equally: Omar Abdel-Wahab, Wenbin Xiao

Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Akihide Yoshimi, Alexander V. Penson, Omar Abdel-Wahab & Wenbin Xiao

  2. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Tanya M. Trippett

  3. Department of Pathology, Buffalo General Medical Center, SUNY at Buffalo, Buffalo, NY, 14206, USA

    Nan Zhang

  4. Department of Laboratory Medicine, University of Washington, Seattle, WA, 98109, USA

    Xueyan Chen

  5. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Alexander V. Penson

  6. Department of Pathology, Hematopathology service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Maria E. Arcila, Janine Pichardo, Jeeyeon Baik, Allison Sigler, Ahmet Dogan & Wenbin Xiao

  7. Department of Pathology, Diagnostic Molecular laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Maria E. Arcila

  8. Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan

    Hironori Harada

  9. Castleman Disease Collaborative Network, Philadelphia, PA, USA

    David C. Fajgenbaum

  10. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Omar Abdel-Wahab

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  1. Akihide Yoshimi
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Contributions

AY, OA-W, and WX designed the study; AY, AVP, MEA, and HH performed experiments; TMT, NZ, and XC provided clinical samples; JP, JB, AS, DCF, and AD coordinated the project; AY, OA-W, and WX prepared the paper with help from all co-authors.

Corresponding author

Correspondence to Wenbin Xiao.

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Conflict of interest

DCF receives research funding from EUSA Pharma for the ACCELERATE Registry (formerly sponsored by Janssen Pharmaceuticals). AD has received personal fees from Roche, Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Peerview Institute, Oncology Specialty Group, Pharmacyclics, Celgene, and Novartis and research grants from National Cancer Institute, Roche. OA-W has served as a consultant for H3 Biomedicine, Foundation Medicine Inc., Merck, and Janssen and serves on the scientific advisory board of Envisagenics Inc.; OA-W has received personal speaking fees from Daiichi Sankyo. OA-W has received prior research funding from H3 Biomedicine unrelated to the current paper. OA-W is an inventor on a provisional patent application submitted by Fred Hutchinson Cancer Research Center that covers BRD9 activation in cancer. WX has received research support from Stemline therapeutics. Other authors have nothing to disclose.

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Yoshimi, A., Trippett, T.M., Zhang, N. et al. Genetic basis for iMCD-TAFRO. Oncogene 39, 3218–3225 (2020). https://doi.org/10.1038/s41388-020-1204-9

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