IMP dehydrogenase rod/ring structures in acral melanomas

Abstract

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH‐based RR structures. Forty‐five ALM paraffin‐embedded tissue samples and 59 melanocytic nevi were probed with anti‐IMPDH2 antibody. Both the rod‐ and ring‐shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR‐positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR‐positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR‐positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR‐positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR‐low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.

IMPDH forms the cytoophidium in zebrafish

“…Thereafter, many other conditions have been shown to promote IMPDH cytoophidium assembly, such as glutamine deficiency, disturbance of one-carbon pathway and treatment by a variety of clinical drugs, implying that cytoophidium formation is correlated with changes in the metabolic state of the cell (Calise et al, 2014;Calise et al, 2016;Keppeke et al, 2016). Yet, the IMPDH cytoophidium is also observed in certain cells and tissues without additional stimulus, such as mouse pluripotent stem cells, antigen-activated T lymphocytes, retinal photoreceptor cells, and some tumors, such as acral melanomas and clear cell renal cell carcinoma (Calise et al, 2018;Duong-Ly et al, 2018;Keppeke et al, 2020;Keppeke et al, 2018;Plana-Bonamaiso et al, 2020;Ruan et al, 2020).…”

The value of anti-rods and rings antibodies in patients with nonhepatitis virus infection

“…Keppeke et al reported a high frequency (91.0%) in 45 acral lentiginous melanoma paraffin-embedded tissue samples and a frequency (39.0%) in 59 melanocytic nevi samples. [ 2 ] In line with these data, Covini et al reported that ant-RR structures had been detected in 15 out of 75 (20%) chronic HCV infection patients. [ 22 ] Stinton et al reported a frequency (4.8%) in 315 chronic HCV infection patients.…”

The clinical value of indirect immunofluorescence for screening anti-rods and rings antibodies: A retrospective study of two centers in China

“…A recent study has shown that cytidine triphosphate synthase (CTPS), which catalyzes the rate-limiting step in the de novo CTP synthetic pathway in which UTP is converted into CTP, also assembles into RR structures ( 53 ). All of them provide a possibility that screening for the presence of the RR pattern can be used to analyze the metabolic status and prognosis of tumors ( 54 ). Unfortunately, we did not observe whether RR pattern is related to tumors in our study, which may be because our clinical data are not detailed enough.…”