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dc.contributor.authorGausdal, Groen_US
dc.contributor.authorWergeland, Anitaen_US
dc.contributor.authorSkavland, Jørnen_US
dc.contributor.authorNguyen, Ericen_US
dc.contributor.authorPendino, Frédéricen_US
dc.contributor.authorRouhee, Nazaninen_US
dc.contributor.authorMcCormack, Emmeten_US
dc.contributor.authorHerfindal, Larsen_US
dc.contributor.authorKleppe, Runeen_US
dc.contributor.authorHavemann, Ursulaen_US
dc.contributor.authorSchwede, Franken_US
dc.contributor.authorBruserud, Øysteinen_US
dc.contributor.authorGjertsen, Bjørn Toreen_US
dc.contributor.authorLanotte, Michelen_US
dc.contributor.authorSégal-Bendirdjian, Evelyneen_US
dc.contributor.authorDøskeland, Stein Oveen_US
dc.PublishedCell Death and Disease 4: e516eng
dc.description.abstractWe show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.en_US
dc.publisherNature Publishing Groupeng
dc.relation.ispartof<a href="" target="blank">Abrogation of Anthracycline and Ischemia-Reperfusion Induced Injury by Cell Signaling Modulators</a>eng
dc.rightsAttribution-NonCommercial-NoDerivs CC BY-NC-NDeng
dc.titleCyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosisen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2013 Macmillan Publishers Limited
dc.source.journalCell Death and Disease

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