Abstract
One in three children diagnosed with cancer has leukemia. Leukemia patients that have mutations in Ikaros (IK), a gene that encodes an anti-leukemic factor, have a poor prognosis despite modern chemotherapy. The neurotransmitter receptors, called vasoactive intestinal peptide (VIP) receptor −1 (VPAC1) and VPAC2, which our laboratory has shown to be transcriptionally regulated by IK, are reversed in some leukemia patients. We hypothesized that VIP signaling in leukemia cells bolsters the anti-leukemic activity of IK, while differentially controls transendothelial migration, a hallmark of leukemic transformation, due to VPAC1 for VPAC2 expression reversal. To gain support for this hypothesis, we first asked whether VIP/VPAC1 signaling affects protein levels and/or isoelectric pools of IK (phosphorylation) by conducting two dimensional (2D) gel electrophoresis followed by western analyses. These studies showed that VIP treatment induced a decline in some IK isoforms in activated but not naive lymphoblastic Hut-78 T cells compared to control. Also, VIP addition blocked the appearance of several activated isoelectric immunoreactive IK species. The second question we asked was whether VIP signaling differentially controlled leukemia cell movement by Boyden Chamber assays. Intriguingly, we discovered that both receptors mediated a chemotactic influence towards VIP, but through different signaling pathways. Collectively, these data support the notion that the nervous system naturally contributes to normal blood cell function, but after leukemogenesis, VIP signaling may exacerbate the leukemia phenotype.
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