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CAMP Agonist Forskolin Is a Potent and Selective Inhibitor of Megakaryocytic Differentiation of Primary Human Hematopoietic Stem Cells

, : CAMP Agonist Forskolin Is a Potent and Selective Inhibitor of Megakaryocytic Differentiation of Primary Human Hematopoietic Stem Cells. Blood 100(11): Abstract No 4173, November 16

The cellular signaling events that govern megakaryocytic differentiation of hematopoietic stem cells (HSCs) are largely unknown. We and others have shown a role for the sustained activation of ERK in megakaryocytic differentiation. Thrombopoietin (Tpo), the primary cytokine involved in megakaryocytic differentiation, has been shown to stimulate ERK activation via both ras-raf1 and rap1-B-raf pathways. Rap1 signaling appears responsible for the sustained phase of ERK activation which has been shown to be particularly important for megakaryocytic differentiation. Rap1 signaling is known to be regulated by cAMP, both by PKA-dependent and recently by PKA-independent mechanisms. In order to investigate the role of cAMP in the regulation of megakaryopoiesis, adult CD34+ G-CSF mobilized HSCs were cultured in the presence or absence of the adenylate cyclase agonist forskolin (Fsk). Low micromolar concentrations of Fsk potently inhibited megakaryocytic differentiation in response to Tpo and the PKC agonist ingenol dibenzoate (IDB). In contrast, erythroid differentiation and myeloid differentiation were unaffected by Fsk. The inhibitory effect appears to be independent of PKA as the PKA inhibitor H89 fail to block the effect of Fsk. Fsk blocked both the early and late phases of ERK activation in response to Tpo and IDB. Interestingly, Fsk failed to block PKC-induced ERK activation or megakaryocytic differentiation in the human erythroleukemia K562 cell line and failed to block ERK activation in response to Tpo in 32Dmpl cells. Overall, the findings suggest that HSC megakaryocytic differentiation is exquisitely sensitive to cAMP formation. This appears to be through mechanisms not shared by certain leukemia cell lines. The inhibition is associated with blockade of ERK activity. The findings further suggest that a non-PKA dependent mechanism is involved, possibly through cAMP-sensitive guanine nucleotide exchange factors such as C3G or epac which are known to regulate rap1 acitivty. These findings also suggest that the therapeutic effect of angrelide (a known phosphodiesterase inhibitor) to inhibit megakaryopoiesis is due to inhibition of ERK activation via elevations of intracellular cAMP levels.


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