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Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-09-2725. This Article Full Text (PDF) All Versions of this Article: 2002-09-2725v1 102/1/237    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Witcher, M. Articles by Miller, W. H Search for Related Content PubMed PubMed Citation Articles by Witcher, M. Articles by Miller, W. H Social Bookmarking                   What's this? Submitted September 6, 2002 Accepted December 23, 2002 Synergy between all trans retinoic acid and tumor necrosis factor pathways in acute leukaemia cells Michael Witcher, Douglas T Ross, Caroline Rousseau, Leslie Deluca, and Wilson H Miller* Lady Davis Institute, Montreal, Quebec, Canada Applied Genomics, Sunnyvale, CA, USA * Corresponding author; email: wmiller{at}ldi.jgh.mcgill.ca.. The nuclear receptor ligand all trans retinoic acid (ATRA) causes dramatic terminal differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients, but is less active in other malignancies. However, downstream mediators of the effects of ATRA are not well understood. We utilized a cDNA microarray to search for ATRA regulated genes in the APL cell line NB4 and found that ATRA regulated several members of the tumor necrosis factor (TNF) pathway. Here we show that TNF can synergize with ATRA to induce differentiation, showing monocytic characteristics more typical of differentiation mediated by TNF than ATRA. ATRA and TNF could also induce differentiation of the non-APL cell line U937. Underlying this response was an increase in TNF induced NF-B DNA binding within 2 hours in the presence of ATRA and activation of NF-B DNA binding and transcriptional activity in response to ATRA alone within 48 hours of ATRA treatment. Furthermore, we found a synergistic induction of the NF-B target genes BCL-3, Dif-2 and TNFR2 in response to the combination of TNF and ATRA. These genes have been previously shown to play a role in TNF signaling and amplification of such genes may represent a mechanism whereby TNF and ATRA can act synergistically. We propose that ATRA can prime cancer cells for differentiation triggered by TNF and suggest that targeting the TNF pathway in combination with ATRA may represent a novel route to treat leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Laurenzana, L. A. Petruccelli, F. Pettersson, M. E. Figueroa, A. Melnick, A. S. Baldwin, F. Paoletti, and W. H. Miller Jr. Inhibition of DNA Methyltransferase Activates Tumor Necrosis Factor {alpha}-Induced Monocytic Differentiation in Acute Myeloid Leukemia Cells Cancer Res., January 1, 2009; 69(1): 55 - 64. [Abstract] [Full Text] [PDF] M. Witcher, F. Pettersson, D. Dupere-Richer, A. Padovani, L. Summers-Deluca, A. S. Baldwin, and W. H. Miller Jr Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter Nucleic Acids Res., February 2, 2008; 36(2): 435 - 443. [Abstract] [Full Text] [PDF] K. Kim, H. H. Kim, J. H. Kim, Y. H. Choi, Y. H. Kim, and J. 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