Activation of Rhoa‐vav1 Signaling in Angioimmunoblastic T‐cell Lymphoma

Abstract

functional annotation was done by gene set enrichment analysis (GSEA).Results: Genes downregulated after ETS1 silencing by siRNAs in 5 ABC DLBCL cell lines (TMD8, HBL-1, U2932, OCI-Ly10, SU-DHL-2) belonged to the signaling of BCR (NES 2.45 FDR <0.001), CD40 (NES 2.67 FDR <0.001), and NFKB/TNFA (NES 2.03 FDR 0.01), as well as to inflammatory response (NES 2.14 FDR 0.005) and differentiation (NES 2.5 FDR <0.001). Three candidate genes were selected for further studies according to the following educated guess criteria: i) potential biologic role; and ii) presence of binding sites for ETS factors in their promoter regions. HCST, RGS1 and FAIM3 were confirmed to be downregulated, by qPCR, also after silencing with shRNA. Their expression in clinical specimens was confirmed in two large series of 181 and 233 DLBCL cases, respectively. FAIM3 expression was higher in ABC DLBCL cases than germinal center type (GCB) DLBCL in both series (P < 0.0001), and a similar pattern was confirmed at protein level in cell lines derived from ABC (n = 6) or GCB DLBCL (n = 8). Conclusions: NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.