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Related Collections Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 February 2002, Vol. 99, No. 3, pp. 1014-1022 NEOPLASIA Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk Qi Zhu, Ji-Wang Zhang, Hai-Qing Zhu, Yu-Lei Shen, Maria Flexor, Pei-Ming Jia, Yun Yu, Xun Cai, Samuel Waxman, Michel Lanotte, Sai-Juan Chen, Zhu Chen, and Jian-Hua Tong From the Shanghai Institute of Hematology and Key Laboratory for Human Genome Research, Rui Jin Hospital, Shanghai Second Medical University, Shanghai, China; INSERM U496, Centre G. Hayem, Hopital Saint Louis, Paris, France; and Division of Neoplastic Diseases, Department of Medicine, The Mount Sinai Medical Center, New York, NY. Acute promyelocytic leukemia (APL) is characterized by the specific chromosome translocation t(15;17) with promyelocytic leukemia-retinoic acid receptor- (PML-RARA) fusion gene and the ability to undergo terminal differentiation as an effect of all-trans retinoic acid (ATRA). Recently, arsenic trioxide (As2O3) has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. At the cellular level, As2O3 triggers apoptosis and a partial differentiation of APL cells in a dose-dependent manner; both effects are observed in vivo among patients with APL and APL animal models. To further explore the mechanism of As2O3-induced differentiation, the combined effects of arsenic and a number of other differentiation inducers on APL cell lines (NB4 and NB4-R1) and some fresh APL cells were examined. The data show that a strong synergy exists between a low concentration of As2O3 (0.25 µM) and the cyclic adenosine monophosphate (cAMP) analogue, 8-CPT-cAMP, in fully inducing differentiation of NB4, NB4-R1, and fresh APL cells. Furthermore, cAMP facilitated the degradation of As2O3-mediated fusion protein PML-RAR, a process considered to play a key role in overcoming the differentiation arrest of APL cells. On the other hand, cAMP could significantly inhibit cell growth by modulating several major players in G1/S transition regulation. Interestingly, H89, an antagonist of protein kinase A, could block the differentiation-inducing effect of As2O3 potentiated by cAMP. These results thus support the existence of a novel signaling cross-talk for APL maturation, which may deepen understanding of As2O3-induced differentiation in vivo, and thus furnish insights for new therapeutic strategies. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z.-Y. Wang and Z. Chen Acute promyelocytic leukemia: from highly fatal to highly curable Blood, March 1, 2008; 111(5): 2505 - 2515. [Abstract] [Full Text] [PDF] A. Catalano, M. A. Dawson, K. Somana, S. Opat, A. Schwarer, L. J. Campbell, and H. Iland The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia Blood, December 1, 2007; 110(12): 4073 - 4076. [Abstract] [Full Text] [PDF] D. Shackelford, C. Kenific, A. Blusztajn, S. Waxman, and R. 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