Abstract 3540: Down-regulation of solute carrier family 17 member 1(SLC17A1) expression contributes to chemotherapy resistance in acute myeloid leukemia

Abstract

Abstract Cytosine arabinoside (Ara-C), an structural analogue of deoxycytidine, is generally considered to be the major drug in the treatment of AML. In acute myeloblastic leukemia (AML) treatment, resistance to cytotoxic nucleoside analogues is a major problem. To investigate novel genes associating with becoming Ara-C resistant cells, whole genome SNP chip analysis was performed. However, there was no significant in Ara-C metabolite genes. In that analysis, 12 region of loss of heterozygote (LOH) was found in non-CR group. SLC17 family gene and HIST1H family gene located in major of LOH in non-CR group. Since SLC29A1 expression levels directly affected the Ara-C mediated Apoptosis, we selected SLC17A1 among them and functional analysis of SLC17A1 was performed. Its expression levels were examined in four different AML cell lines using RT-PCR. Its expression level was a little different but that gene seemed to be constitutively expressed. To detect the pattern change of SLC17A1 in survival AML cells against Ara-C treatments, four AML cell-lines underwent 10−8 M of Ara-C addition/ depletion for 2 and 4 cycles. The results showed that expression of SLC17A1 was decreased more than SLC29A1 expression in the same treated condition. To examine whether the expression levels of SLC17A1 was associated with Ara-C resistance, Ara-C resistant HEL cell was established in vitro and in vivo (HEL-R1 and HEL-R1-vivo). Our results indicated that SLC17A1 mRNA expression of both resistant cells is decreased or less increased than HEL cells in Ara-C treatment. And the reduction of SLC17A1 mRNA by shRNA of SLC17A1 effectively suppressed Ara-C mediated apoptosis. Our results suggested that the function of SLC17A1 gene was similar to that of SLC29A1. Taken together, the expression levels of SLC17A1 also might involve the cytotoxic effects of Ara-C treatment. SLC17A1 could be a novel gene controlling Ara-C mediated apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3540.