Abstract 1607: Quantitative membrane proteome profiling to discover therapeutic targets for adult T-cell leukemia (ATL)

Abstract

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is one of retroviruses known as the causative agent of adult T-cell leukemia (ATL), which is infected within 20 million people in the world. ATL develops at the prevalence of only 5% among HTLV-1-infected individuals after a long latency period over 30 years. However, the outcomes of conventional treatment for ATL are not satisfactory, exhibiting overall 5-year survival rate of 20%. To discover novel therapeutic targets for ATL, we performed label-free quantitative membrane proteome analysis for CD4+ T-cell subpopulation in which HTLV-1 infected cells are enriched. Tryptic digests of CD4+ T-cells were prepared from 14 normal donors (ND), 21 asymptomatic carriers (AC), and 13 ATL patients. To focus on the membrane derived peptides, glycosylated peptides were enriched by lectin column chromatography (Mol Cell Proteomics. 2010,9(9),1819) since most of membrane proteins are glycosylated. The eluates were analyzed by LC/MS/MS and 8,658 N-glycosylated peptides derived from 1,134 N-glycosylated proteins were identified. The therapeutic targets were subsequently extracted by a couple of criteria as follows. The all-or-nothing analysis explored peptides detected in none or 1 case of ND+AC group, resulting in identification of 31 peptides derived from 19 proteins. Additionally Welch's t-test (ATL vs. ND+AC) identified 33 peptides derived from 14 proteins (p < 0.05 and fold change > 2.0). The identified therapeutic target molecules above included cell adhesion molecule 1 (CADM1 or TSLC1) which overexpresses in ATL cells and induces organ infiltration of tumor cells. Programmed cell death 1 ligand 1 (PD1L1) was also found in our therapeutic target list, which was known to be up-regulated in ATL cells and involved in induction of immune tolerance. These facts strongly emphasize the credibility of our quantitative profiling results. We would like to show the results of functional inhibitory experiments for novel therapeutic targets and discuss the uncovered molecular mechanisms of ATL progression. Note: This abstract was not presented at the meeting. Citation Format: Makoto Ishihara, Natsumi Araya, Tomoo Sato, Risa Fujii, Ayako Tatsuguchi, Naomi Saichi, Hidewaki Nakagawa, Yoshihisa Yamano, Koji Ueda. Quantitative membrane proteome profiling to discover therapeutic targets for adult T-cell leukemia (ATL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1607. doi:10.1158/1538-7445.AM2014-1607