Genetic basis for iMCD-TAFRO

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 P128L mutation and a germline RUNX1 G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2 P128L 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 G60C 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.

A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease

“…Overall, molecular aberrations were identified in 111 patients, which included seven cases with cytogenetic abnormalities and 104 cases with molecular data. The clinical characteristics and genetic abnormalities for each case are shown in Supplemental Tables S1 and S2 [ 7 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. The female-to-male ratio was 21:24 for iMCD and 40:14 for UCD cases; of note, the study from Chang et al [ 29 ] was composed entirely of female patients.…”

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry

“…Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS)‐associated MCD involves excessive cytokine production by a monoclonal plasma cell population. Human herpesvirus‐8 (HHV8)‐associated MCD is a lymphoproliferative disorder caused by uncontrolled proliferation of HHV8‐infected plasma cells/plasmablasts and HHV8‐driven cytokine dysregulation, 7‐9 whereas idiopathic MCD (iMCD) involves a similar cytokine storm — in which interleukin (IL)‐6 is a key driver in many cases — but has an unknown aetiology and an emerging understanding of pathogenesis 10‐17 …”

Multicentric Castleman disease and the evolution of the concept

“…A somatic MAP2K2 (MEK2) mutation and a germline RUNX1 mutation were identified in two patients with TAFRO-iMCD. In both patients, ERK was significantly activated, suggesting a potential role of the MAPK signaling in the pathogenesis of TAFRO-iMCD 78 .…”