Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. Kawabata H, Takai K, Kojima M, Nakamura N, Aoki S, Nakamura S, et al. Castleman-Kojima disease (TAFRO syndrome): a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly: a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). J Clin Exp Hematop. 2013;53:57–61.

  2. Inoue M, Ankou M, Hua J, Iwaki Y, Hagihara M, Ota Y. Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A: a case report. J Clin Exp Hematop. 2013;53:95–9.

    Article  Google Scholar 

  3. Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 2016;91:220–6.

    Article  CAS  Google Scholar 

  4. Iwaki N, Gion Y, Kondo E, Kawano M, Masunari T, Moro H, et al. Elevated serum interferon gamma-induced protein 10 kDa is associated with TAFRO syndrome. Sci Rep. 2017;7:42316.

    Article  CAS  Google Scholar 

  5. Pierson SK, Stonestrom AJ, Shilling D, Ruth J, Nabel CS, Singh A, et al. Plasma proteomics identifies a ‘chemokine storm’ in idiopathic multicentric Castleman disease. Am J Hematol. 2018;93:902–12.

    Article  CAS  Google Scholar 

  6. Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, van Rhee F, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3:e163–75.

    Article  Google Scholar 

  7. Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129:1646–57.

    Article  CAS  Google Scholar 

  8. Ozkaya N, Rosenblum MK, Durham BH, Pichardo JD, Abdel-Wahab O, Hameed MR, et al. The histopathology of Erdheim-Chester disease: a comprehensive review of a molecularly characterized cohort. Mod Pathol. 2018;31:581–97.

    Article  CAS  Google Scholar 

  9. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.

    Article  CAS  Google Scholar 

  10. Yoshimi A, Toya T, Nannya Y, Takaoka K, Kirito K, Ito E, et al. Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan. Ann Oncol. 2016;27:887–95.

    Article  CAS  Google Scholar 

  11. Nagy A, Bhaduri A, Shahmarvand N, Shahryari J, Zehnder JL, Warnke RA, et al. Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas. Blood Adv. 2018;2:481–91.

    Article  CAS  Google Scholar 

  12. Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559:400–4.

    Article  CAS  Google Scholar 

  13. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  Google Scholar 

  14. Baker TS, Gambino KJ, Schriefer L, Lim JY, Steinberg KM, Fajgenbaum DC, et al. A novel FAS mutation with variable expressivity in a family with unicentric and idiopathic multicentric Castleman disease. Blood Adv. 2018;2:2959–63.

    Article  CAS  Google Scholar 

  15. Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010;87:873–81.

    Article  CAS  Google Scholar 

  16. Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.

    Article  CAS  Google Scholar 

  17. Yoshimi A, Lin KT, Wiseman DH, Rahman MA, Pastore A, Wang B, et al. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature. 2019;574:273–7.

    Article  CAS  Google Scholar 

  18. Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, et al. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Blood. 2011;117:3617–28.

    Article  CAS  Google Scholar 

  19. Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99:1364–72.

    Article  CAS  Google Scholar 

  20. Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14:22–9.

    Article  CAS  Google Scholar 

  21. Li Z, Lan X, Li C, Zhang Y, Wang Y, Xue W, et al. Recurrent PDGFRB mutations in unicentric Castleman disease. Leukemia. 2019;33:1035–8.

    Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoshimi, A., Trippett, T.M., Zhang, N. et al. Genetic basis for iMCD-TAFRO. Oncogene 39, 3218–3225 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links