Abstract
Leukemia is cancer of the blood that results in 50,000 deaths annually in the US. A majority of leukemias have mutations/deletions in either Notch or Ikaros genes, which encode transcriptional regulators that recognize the same DNA sequence. Notch/Ikaros binding sites are found >10 times in the promoter regions (5kb) of vasoactive intestinal peptide receptor 1 (VPAC1) and VPAC2. These neuropeptide G‐protein coupled receptors transmit growth regulating signals when bound to their ligand. Lymphocytes are normally in a quiescent state with a high VPAC1:VPAC2 ratio. However, upon a mitogenic signal (i.e. T cell activation) the anti‐proliferative VPAC1 “shield” is lost and the VIP receptor ratio becomes equalized. We hypothesized that leukemia cells (hyperproliferative phenotype) would have a greater skewing in favor of the anti‐apoptotic VPAC2 receptor. To this end, total RNA was isolated from human leukemia tumors and cell lines, and VIP receptor mRNA levels were measured by SYBR green qPCR. In support of our hypothesis, T cell leukemia revealed a dramatic receptor reversal, downregulating VPAC1 and upregulating VPAC2. Similarly, B cell leukemia also showed VIP receptor dysregulation. We concluded that a shift from an anti‐proliferative to an anti‐apoptotic phenotype is driven by VIP receptor expression changes. This work was supported by COBRE (2P20RR015566) and NIH/NIDDK Career Award (KO11K01DK064828).
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