Inhibitors of type 4 cAMP phosphodiesterase (PDE4) such as rolipram-induced apoptosis in B cell chronic lymphocytic leukemia, even in the absence of exogenous pharmacologic agents that activate adenylate cyclase such as the diterpene forskolin. T cells or T-CLL, in contrast, are resistant to rolipram-induced apoptosis. Rolipram induces a mitochondrial death pathway in B-CLL cells, perhaps in part due to activation of the phosphatase PP2A and dephosphorylation of BAD. Remarkably, cAMP can also activate an antiapoptotic pathway in B-CLL through EPAC1, a cAMP-activated Rap1 GDP exchange factor. B-CLL cells are unique among circulating hematopoietic cells in their functional expression of EPAC1, suggesting EPAC1 signaling may play a role in the pathophysiology of this disease.
Specific Aim I. To elucidate the mechanism by which PDE4 inhibitors activate a mitochondrial pathway of apoptosis in B-CLL, we will: A) Determine whether PDE4 inhibitor-induced apoptosis in CLL is PKA-mediated. B) Determine whether rolipram-induced apoptosis in CLL is EPAC-independent. C) Determine the mechanism for rolipram-induced augmented CLL PP2A activity. D) Determine whether PP2A is required for rolipram-mediated apoptosis in CLL.
Specific Aim II. To contrast the roles of EPAC and PKA signaling in CLL, we will: A) Determine whether PKA activation by PDE4 inhibitors blocks the ability of EPAC activation to augment B-CLL chemokine transcript levels. B) Determine if EPAC-induced augmentation of chemokine and/or Mcl-1 transcripts is unique to B-CLL among circulating hematopoietic cells. C) Determine if EPAC-induced augmentation of B-CLL survival results from up-regulation of an IL-8 autocrine loop. D) Determine whether PKA and EPAC differentially regulate PI3K or its downstream targets.
Specific Aim III. To determine whether the unique expression of functional EPAC in CLL cells is of pathophysiologic importance, we will: A) Examine the effects of EPAC activation on CLL adhesion and migration. B) Compare the effects of EPAC and PKA activation on both basal and chemotherapy-induced CLL survival. C) Compare the effects of EPAC and PKA on CLL and B cell proliferation.
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