Abstract 5867: Transcriptome profiling of ST3GAL4 and FUT7 in multiple tumor types and prognostic value in adult acute myeloid leukemia

Abstract

Abstract E-selectin is a cell adhesion glycoprotein expressed on endothelial cells and participates in the development of environmental-mediated drug resistance and poor clinical outcome in cancer. The E-selectin antagonist, uproleselan, interrupts leukemic cell homing to the vascular niche and increases susceptibility to cytotoxic therapies. Recent clinical data demonstrate a correlation between leukemic cell surface E-selectin ligands and response to uproleselan, linking E-selectin ligand expression to response. Multiple genes involved in the glycan synthesis of E-selectin ligands are highly expressed in pediatric AML. Expression levels of two of these genes, ST3GAL4 and FUT7 are associated with poor outcome and are associated with cell surface E-selectin ligand expression. In the current studies we extend transcriptome profiling of E-selectin ligand forming glycosylation genes with an emphasis on ST3GAL4 and FUT7 in different cancers. Initially, we investigated expression levels of ST3GAL4 and FUT7 in 10,258 samples covering 33 cancer types from the TCGA PanCanAtlas. ST3GAL4 and FUT7 were consistently expressed in the majority of cancers evaluated. The cancer types that expressed ST3GAL4 most highly were melanoma (uveal and skin), kidney chromophobe, adrenocortical carcinoma and bladder urothelial carcinoma, while for FUT7, it was AML, diffuse large B-cell lymphoma, thymoma, testicular germ cell tumors and head and neck squamous cell carcinoma. Of particular interest was the identification of adult AML for the highest expression of FUT7 and high expression of ST3GAL4 (mean log2 gene expression = 8.1 and 9.4, respectively). Augmented expression of FUT7 and ST3GAL4 were also observed in an analysis of 39 AML cell lines among the 1,457 cell lines comprising the Cancer Cell Line Encyclopedia RNAseq data set. The prognostic significance of FUT7 and ST3GAL4 in adult AML was further assessed using the TCGA-LAML RNAseq dataset for differential expression and associations with overall survival (OS). The data set included 151 RNAseq profiles of bone marrow samples from adult patients with AML, and within this data set the status of the FMS-like tyrosine kinase 3 (FLT3) proto-oncogene was considered. Mutational alterations of FLT3 are associated with higher risk of relapse and shorter OS compared with wild-type FLT3. ST3GAL4 and FUT7 were both identified as being upregulated (fold-change = 1.73 and 1.40, respectively) in the mutated FLT3 subset (n=46) as compared to wild type FLT-3 (p=0.000033 and 0.046, respectively). Notably in the mutated FLT-3 subset expression of FUT7 was significantly associated with a poor prognosis and decreased OS (HR = 4.56, p= 0.015). Collectively, these studies extend the prognostic importance of the E-selectin ligand glycosylation genes, ST3GAL4 and FUT7, to adult AML where these genes may be useful as predictive biomarkers. In addition, these studies suggest potential additional tumor types beyond AML where treatment protocols with uproleselan may have therapeutic benefits. Citation Format: William E. Fogler, Vince Deng, David Stewart, Michael Jarman, Simone Daminelli, Adrian Carr, John L. Magnani. Transcriptome profiling of ST3GAL4 and FUT7 in multiple tumor types and prognostic value in adult acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5867.