Figure 1.
SUMO pathway is activated in MM and associated with poor prognosis. (A) Heatmap and hierarchical clustering of the SUMO core components SAE1, UBA2, UBE2I, SUMO1, SUMO2, and SUMO3 derived from transcriptome data from n = 768 patients with MM of MMRF-CoMMpass data; the data were clustered as indicated into SUMOhigh and SUMOlow groups. (B) Kaplan-Meier curves for probability of survival of SUMOhigh and SUMOlow groups as described in panel A. Curve comparison by log-rank test with indicated P value. (C) Immunoblot depicting expression of SUMO2/3 and SUMO1 in healthy CD138+ cells and CD138+ MM cells, which have been isolated from human specimen by magnetic-activated cell sorting. β-Actin served as loading control. (D) Top: a cohort of n = 13 patients with MM, biopsied at diagnosis, subsequently treated, and biopsied again after disease relapse. Biopsied material was subsequently used for transcriptome profiling. Bottom: Gene set enrichment analysis using the fgsea package reveals enrichment of indicated Reactome SUMOylation signatures of relapsed vs newly diagnosed patients with MM. (E) Top: schematic depiction of the CFZ resistance RNA interference (RNAi) resistance screen performed by Acosta-Alvear et al.35 Bottom: Enrichment indicated SUMOylation signatures upregulated in CFZ-resistant compared with CFZ-sensitive U266 cells, determined by fgsea package using the Reactome knowledgebase. (F) Top: schematic depiction of the applied strategy to cultivate CFZ-resistance MM cells. CFZ-sensitive cells were cultured in CFZ-containing medium, slowly increasing the concentration (1-2 weeks) of CFZ until cells became resistant (total duration >12 weeks). Bottom: immunoblot showing expression of SUMO2/3 and SUMO1 in AMO1 and JJN3 CFZ-resistant cells (R) compared with AMO1 and JJN3 parental (P) cells. P cells were treated with 1 μM subasumstat and/or 12 nM CFZ for 4 hours; dimethyl sulfoxide served as vehicle control (-). Resistant cells were cultured in the presence of 12 nM CFZ and cotreated with 1 μM subasumstat as indicated. Cotreatment with subasumstat depletes SUMOylation. Adjusted P values (false discovery rate), ∗P < .05, ∗∗P < .01, ∗∗∗P < .001 (panels D-E). mRNA, messenger RNA; NES, normalized enrichment score; P-adj, adjusted P value; Suba, subasumstat.

SUMO pathway is activated in MM and associated with poor prognosis. (A) Heatmap and hierarchical clustering of the SUMO core components SAE1, UBA2, UBE2I, SUMO1, SUMO2, and SUMO3 derived from transcriptome data from n = 768 patients with MM of MMRF-CoMMpass data; the data were clustered as indicated into SUMOhigh and SUMOlow groups. (B) Kaplan-Meier curves for probability of survival of SUMOhigh and SUMOlow groups as described in panel A. Curve comparison by log-rank test with indicated P value. (C) Immunoblot depicting expression of SUMO2/3 and SUMO1 in healthy CD138+ cells and CD138+ MM cells, which have been isolated from human specimen by magnetic-activated cell sorting. β-Actin served as loading control. (D) Top: a cohort of n = 13 patients with MM, biopsied at diagnosis, subsequently treated, and biopsied again after disease relapse. Biopsied material was subsequently used for transcriptome profiling. Bottom: Gene set enrichment analysis using the fgsea package reveals enrichment of indicated Reactome SUMOylation signatures of relapsed vs newly diagnosed patients with MM. (E) Top: schematic depiction of the CFZ resistance RNA interference (RNAi) resistance screen performed by Acosta-Alvear et al.35 Bottom: Enrichment indicated SUMOylation signatures upregulated in CFZ-resistant compared with CFZ-sensitive U266 cells, determined by fgsea package using the Reactome knowledgebase. (F) Top: schematic depiction of the applied strategy to cultivate CFZ-resistance MM cells. CFZ-sensitive cells were cultured in CFZ-containing medium, slowly increasing the concentration (1-2 weeks) of CFZ until cells became resistant (total duration >12 weeks). Bottom: immunoblot showing expression of SUMO2/3 and SUMO1 in AMO1 and JJN3 CFZ-resistant cells (R) compared with AMO1 and JJN3 parental (P) cells. P cells were treated with 1 μM subasumstat and/or 12 nM CFZ for 4 hours; dimethyl sulfoxide served as vehicle control (-). Resistant cells were cultured in the presence of 12 nM CFZ and cotreated with 1 μM subasumstat as indicated. Cotreatment with subasumstat depletes SUMOylation. Adjusted P values (false discovery rate), ∗P < .05, ∗∗P < .01, ∗∗∗P < .001 (panels D-E). mRNA, messenger RNA; NES, normalized enrichment score; P-adj, adjusted P value; Suba, subasumstat.

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