The Cation Transporter SLC22A16 Is Expressed in Pediatric Acute Lymphoblastic Leukemia

Abstract

Hydrophilic drugs require transport proteins to traverse the cell membrane, and the selective expression of these membrane transporters can confer selective sensitivity to their toxic substrates. Therefore, identification of a transport gene with restricted expression on tumor cells represents an opportunity to target that transporter with a selective, toxic substrate. We previously have demonstrated that the organic cation transport gene SLC22A16 (OCT6) is highly expressed in the leukemia cell line HL-60, and its RNA levels were at least 2 orders of magnitude higher in 25 unique specimens of adult leukemic blasts than in liver, placenta and kidney, the tissues that usually have high expression of SLC22 transporters (Gong, S. et al. Experimental Hematology , 30, 1–8, 2002). To determine the relevance of SLC22A16 gene expression in pediatric acute lymphoblastic leukemia (ALL), we examined its expression using an Affymetrix U133B gene expression microarray in 132 primary pediatric ALL specimens. SLC22A16 was broadly and highly expressed in these pediatric ALL primary specimens. The gene was represented by 2 probesets, with average expression levels of 922 ± 344 in one probeset and 1715 ± 857 in the other. Analysis of subgroups revealed that overall expression was highest in hyperdiploid (>50) ALL specimens (n=17), and lowest in T cell ALL (n=14). The gene with highest correlation with SLC22A16 on the U133B array was ERG (Pearson p=2.4 × 10−8; False Discovery Rate (FDR) =5.2 × 10−5), a member of the Ets family of transcription factors that are implicated in leukemogenesis. MLL gene expression correlated with SLC22A16 expression with a Pearson p=3.3 × 10−5 and FDR=0.005. Other genes of special interest in leukemia biology with significant expression correlation to SLC22A16 included LIMD1, a member of the ZYXIN family (Pearson p=2.3 × 10−6, FDR=0.001), PPAR-alpha (Pearson p=4.5 × 10−7, FDR=0.0004), and STS-1 (Pearson p=7 × 10−7, FDR=0.0005). To examine protein expression of SLC22A16 in pediatric ALL, a polyclonal antibody to SLC22A16, that recognizes a protein of expected size in HL-60 cells, demonstrated expression of this protein at a level comparable to HL-60 cells in 3 of 6 primary pediatric B-precursor ALL specimens. These results suggest that an SLC22A16 substrate plays a physiologic role in pediatric ALL, and that SLC22A16 is a new therapeutic target for pediatric ALL that could be exploited by SLC22A16-specific toxins and antibodies.