UC San Diego

Chronic lymphocytic leukemia (CLL) is associated with the accumulation of B-cells due to decreased apoptosis. CLL is classified as aggressive (rapidly progressive) or indolent (slow-growing). This thesis sought to assess expression of G protein-coupled receptors (GPCRs), in particular GPCRs that regulate the synthesis of the second messenger 3'5'- cyclic adenosine monophosphate (cAMP), in samples from patients with CLL and in normal human B cells. Using a Taqman® GPCR array, we found that normal B-cells, indolent -CLL cells and aggressive-CLL cells express >117 GPCRs, many of which were differentially expressed in CLL-cells and in the two stages of CLL. Expression of the vasoactive intestinal polypeptide receptor 1 (VIPR1) was >700-fold greater in aggressive CLL cells than in indolent CLL-cells and normal B-cells; the agonist (VIP, 1 [mu]M) in combination with a phosphodiesterase 4/7 inhibitor (IR284, 100 nM) raised cAMP levels in both indolent and aggressive CLL-cells, but not in normal B-cells. In addition, VIP treatment (48 hr alone and together with IR284) induces apoptosis in aggressive CLL-cells. The melanocortin 2 receptor MC2R) was expressed in aggressive and indolent CLL-cells but not normal B-cells. Treatment with the MC2R agonist, adrenocorticotropic hormone (ACTH, 1 nM), in combination with IR284 induced apoptosis in aggressive CLL -cells, but not in indolent CLL-cells or normal B-cells. These results reveal that expression of particular GPCRs can provide stage-specific markers and identify novel therapeutic targets for the treatment of CLL. Moreover, the results identify a paradigm that may be useful in other disease settings