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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3335-3342. Prepublished online as a Blood First Edition Paper on July 15, 2004; DOI 10.1182/blood-2004-01-0023. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-01-0023v1 104/10/3335    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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., Jr Related Collections Neoplasia Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells Michael Witcher, Hoi Ying Shiu, Qi Guo, and Wilson H. Miller, Jr From the Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Retinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells. (Blood. 2004;104:3335-3342) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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]

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