title: In vivo activation of cAMP signaling induces growth arrest and differentiation in acute promyelocytic leukemia.
abstract: Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As(2)O(3)). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As(2)O(3)-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As(2)O(3)-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As(2)O(3)-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA-As(2)O(3) therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach.
authors.affiliation: CNRS UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, affilié à l'Université de ParisVII, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Guillemin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Dominique
authors.initials: D
authors.lastname: Vitoux
authors.forename: Scott
authors.initials: S
authors.lastname: Kogan
authors.forename: Hassane
authors.initials: H
authors.lastname: Soilihi
authors.forename: Valérie
authors.initials: V
authors.lastname: Lallemand-Breitenbach
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Daniel
authors.forename: Bernard
authors.initials: B
authors.lastname: Gourmel
authors.forename: Laurent
authors.initials: L
authors.lastname: Degos
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Michel
authors.initials: M
authors.lastname: Lanotte
authors.forename: Hugues
authors.initials: H
authors.lastname: De Thé
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010087:Oxides / Q000494:pharmacology; D015398:Signal Transduction; D013806:Theophylline / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D013806:Theophylline; D000242:Cyclic AMP; D000077237:Arsenic Trioxide