The Journal of Experimental Medicine
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Published 18 November 2002. doi:10.1084/jem.20021129
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© Rockefeller University Press, 0022-1007/2002/11/1373/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 10, November 18, 2002 1373-1380
In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia

Marie-Claude Guillemin1, Emmanuel Raffoux2, Dominique Vitoux1, Scott Kogan7, Hassane Soilihi1, Valérie Lallemand-Breitenbach1, Jun Zhu1, Anne Janin3, Marie-Thérèse Daniel4, Bernard Gourmel5, Laurent Degos2, Hervé Dombret2, Michel Lanotte6 and Hugues de Thé1,5

1 CNRS UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, affilié à l'Université de ParisVII, the
2 Service Clinique des Maladies du Sang, Hôpital St. Louis, 75475 Paris, France
3 ERM 0220, Hôpital St. Louis, 75475 Paris, France
4 Service d'Hématologie Biologique, Hôpital St. Louis, 75475 Paris, France
5 Service de Biochimie, Hôpital St. Louis, 75475 Paris, France
6 INSERM U 496, Hôpital St. Louis, 75475 Paris, France
7 Comprehensive Cancer Center and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94143

Address correspondence to H. de Thé, CNRS UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, affilié à l'Université de ParisVII, Hôpital Saint Louis 1, Avenue Claude Vellefaux, Paris, CEDEX 10, France. Phone: 33-1-53-7221-91; Fax: 33-1-53-7221-90; E-mail: dethe{at}chu-stlouis.fr

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 (As2O3). 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 As2O3-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 As2O3-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 As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 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.

Key Words: theophylline • arsenic • retinoic acid • transgenic mice • clinical trial


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