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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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
Nature Reviews Disease Primers (2021)