One in three children diagnosed with cancer has leukemia. Leukemia patients with mutations in the tumor suppressor transcription factor Ikaros (IK), an anti-leukemic factor that is critical for the development of blood cells; have a poor prognosis despite modern chemotherapy. There is, therefore, a critical need to understand the biology of IK. Research by our laboratory has identified a neurotransmitter, called vasoactive intestinal peptide (VIP), which blocks proliferation through one of its receptors (vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide receptor 1(VPAC1)), but blocks apoptosis through a second inducible receptor (VPAC2), while both receptors have chemotactic properties in primary T cells. Some leukemia patients have reversed VIP receptor expression (low VPAC1; high VPAC2), and we hypothesizes that this contributes to a selective growth advantage. Understanding the biology by which VIP receptors regulate cellular growth (proliferation and apoptosis) and movement (chemotaxis) will be pivotal in establishing their signaling pathways as future drugs target candidates in the fight against leukemia. We hypothesized that VIP/VPAC1 signaling would alter the expression of IK protein and that VIP would direct cellular migration of both VPAC1 and VPAC2 expressing leukemic T cells. To test this hypothesis, we first asked whether VIP/VPAC1 signaling affects the expression and/or the phosphorylation profile of IK a transcription factor that regulates cellular growth. The second question was whether VPAC1 and/or VPAC2 signaling differentially control leukemic cell movement. By one- and two-dimensional polyacrylamide gel electrophoresis followed by Western blot analysis, we showed that VIP signaling suppresses IK expression and changes the isoelectric pools of IK protein in a human leukemia cell line. By using leukemia cells that only express VPAC1 or VPAC2 receptors; we demonstrated that VIP promoted cellular movement, but that this effect was controlled by different pathways elicited by VPAC1 versus VPAC2. Collectively, these data support the notion that the nervous system naturally contributes to normal blood cell function, but after leukemogenesis, the VIP signaling axis may exacerbate the leukemia phenotype.