{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:52:19Z","timestamp":1791147139580,"version":"4.1.0"},"reference-count":36,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Type 4 cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE4) inhibitors and other agents that raise intracellular cAMP levels induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) but not in T-CLL or peripheral blood T cells. Two principal effector proteins for cAMP are protein kinase A (PKA) and EPAC (exchange protein directly activated by cAMP), a Rap guanosine 5\u2032-diphosphate (GDP) exchange factor. We here examine whether varying expression of EPAC accounts for the discrepant sensitivity of B-CLL and T cells to PDE4 inhibitor-induced apoptosis. B-CLL and peripheral blood B cells express EPAC1 transcript, whereas T-CLL, peripheral blood T cells, monocytes, and neutrophils do not. Treatment with the PDE4 inhibitor rolipram induces Rap1 activation in B-CLL cells but not in peripheral blood B cells, T-CLL, or any of the normal hematopoietic lineages examined. The EPAC-specific cAMP analog 8CPT-2Me-cAMP (8-(4-chloro-phenylthio)-2\u2032-O-methyladenosine-3\u2032,5\u2032-cAMP) activates Rap1 in B-CLL cells, but, unlike rolipram\/forskolin or 8-Bromo-cAMP, it does not induce PKA activation, as judged by phosphorylation of the transcription factor cAMP-response element binding protein (CREB). Unexpectedly, whereas rolipram\/forskolin and 8-Bromo-cAMP induce apoptosis in B-CLL cells, 8CPT-2Me-cAMP decreased basal apoptosis in B-CLL cells by an average of 25% (P &amp;lt; .002). Our results demonstrate that B-CLL cells uniquely activate Rap1 in response to PDE4 inhibitors and suggest that physiologic stimuli that activate EPAC may transmit an antiapoptotic signal. (Blood. 2004;103:2661-2667)<\/jats:p>","DOI":"10.1182\/blood-2003-06-2154","type":"journal-article","created":{"date-parts":[[2003,11,18]],"date-time":"2003-11-18T01:14:02Z","timestamp":1069118042000},"page":"2661-2667","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":64,"title":["Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis"],"prefix":"10.1182","volume":"103","author":[{"given":"Sanjay","family":"Tiwari","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriacos","family":"Felekkis","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Yi","family":"Moon","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Flies","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Sherr","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Lerner","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; Departments of Pathology and Microbiology, Boston University School of Medicine, Boston, MA; and the Department of Environmental Health, Boston University School of Public Health, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021218221413300_REF1","doi-asserted-by":"crossref","unstructured":"Epstein PM, Moraski S, Hachisu R. 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