Decreased RORC expression and downstream signaling in HTLV-1-associated Adult T-cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy?

Abstract

Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma (ATL), but RORC (Retinoic acid Orphan Receptor C) signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in Human T-cell Leukemia Virus-1 (HTLV-1) infection and ATL, using our own and publicly available gene expression data for ATL and other leukemias, HTLV-1-infected individuals and healthy controls. Gene expression data from ATL patients were analyzed using Weighted Gene Correlation Network Analysis (WGCNA) to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T-cells showed decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. In addition, an age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/MKI67), whereas downstream members clustered in an antiproliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute leukemias. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.AbbreviationsHTLV-1Human T-cell Leukemia Virus-1ATLAdult T-cell Leukemia/LymphomaWGCNAWeighted Gene Correlation Network AnalysisATRAAll-trans retinoic acidRARaRetinoic acid receptor alphaRORCRetinoic acid orphan receptor CTBLVType B Leukomogenic VirusAMLAcute Myeloid LeukemiaT-ALLT-cell acute lymphoblastic leukemiaILInterleukinPCNAProliferating cell nuclear antigenIDInfectious Dermatitis

XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis

“…We and others have previously demonstrated that a combined in vitro, ex vivo and in silico approach might recapitulate the ATL in vivo response [16][17][18][19] . In addition, we have also shown that HTLV-1-transformed MT-2 and MT-4 cells phenocopy primary ATL cells 18 in their relative resistance to the antiproliferative and proapoptotic effects of IFN-α 16,17 .…”