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This Article Full Text Full Text (PDF) 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 DiMartino, J. F. Articles by Shilatifard, A. Search for Related Content PubMed PubMed Citation Articles by DiMartino, J. F. Articles by Shilatifard, A. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 December 2000, Vol. 96, No. 12, pp. 3887-3893 NEOPLASIA A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL Jorge F. DiMartino, Trissa Miller, Paul M. Ayton, Theresa Landewe, Jay L. Hess, Michael L. Cleary, and Ali Shilatifard From the Department of Pathology and the Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford, CA; the Department of Biochemistry, St Louis University School of Medicine, St Louis, MO; and the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA. The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid leukemias fuses the gene encoding transcriptional elongation factor ELL to the MLL gene with consequent expression of an MLL-ELL chimeric protein. To identify potential mechanisms of leukemogenesis by MLL-ELL, its transcriptional and oncogenic properties were investigated. Fusion with MLL preserves the transcriptional elongation activity of ELL but relocalizes it from a diffuse nuclear distribution to the nuclear bodies characteristic of MLL. Using a serial replating assay, it was demonstrated that the MLL-ELL chimeric protein is capable of immortalizing clonogenic myeloid progenitors in vitro after its retroviral transduction into primary murine hematopoietic cells. However, a structure-function analysis indicates that the elongation domain is not essential for myeloid transformation because mutants lacking elongation activity retain a potent ability to immortalize myeloid progenitors. Rather, the highly conserved carboxyl terminal R4 domain is both a necessary and a sufficient contribution from ELL for the immortalizing activity associated with MLL-ELL. The R4 domain demonstrates potent transcriptional activation properties and is required for transactivation of a HoxA7 promoter by MLL-ELL in a transient transcriptional assay. These data indicate that neoplastic transformation by the MLL-ELL fusion protein is likely to result from aberrant transcriptional activation of MLL target genes. Thus, in spite of the extensive diversity of MLL fusion partners, these data, in conjunction with previous studies of MLL-ENL, suggest that conversion of MLL to a constitutive transcriptional activator may be a general model for its oncogenic conversion in myeloid leukemias. © 2000 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: Y.-H. Lin, P. M. Kakadia, Y. Chen, Y.-Q. Li, A. J. Deshpande, C. Buske, K.-L. Zhang, Y. Zhang, G.-L. Xu, and S. K. Bohlander Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias Blood, July 16, 2009; 114(3): 651 - 658. [Abstract] [Full Text] [PDF] J. Zhou, X. Feng, B. Ban, J. Liu, Z. Wang, and W. Xiao Elongation Factor ELL (Eleven-Nineteen Lysine-rich Leukemia) Acts as a Transcription Factor for Direct Thrombospondin-1 Regulation J. Biol. 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DiMartino, P. M. Ayton, E. H. Chen, C. C. Naftzger, B. D. Young, and M. L. Cleary The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10 Blood, May 15, 2002; 99(10): 3780 - 3785. [Abstract] [Full Text] [PDF] M. Birke, S. Schreiner, M.-P. Garcia-Cuellar, K. Mahr, F. Titgemeyer, and R. K. Slany The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation Nucleic Acids Res., February 15, 2002; 30(4): 958 - 965. [Abstract] [Full Text] [PDF] R. T. Luo, C. Lavau, C. Du, F. Simone, P. E. Polak, S. Kawamata, and M. J. Thirman The Elongation Domain of ELL Is Dispensable but Its ELL-Associated Factor 1 Interaction Domain Is Essential for MLL-ELL-Induced Leukemogenesis Mol. Cell. Biol., August 15, 2001; 21(16): 5678 - 5687. [Abstract] [Full Text] [PDF] U. Fuchs, G. Rehkamp, O. A. Haas, R. Slany, M. Konig, S. Bojesen, R. M. Bohle, C. Damm-Welk, W.-D. Ludwig, J. Harbott, et al. 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