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Molecular Biology, Pathobiology and Genetics |
Departments of 1 Pathology and Laboratory Medicine and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 2 Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada; and 3 Department of Genetics, University of Erlangen, Erlangen, Germany
Requests for reprints: Jay L. Hess, Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, M5240 Medical Science 1, Ann Arbor, MI 48109-0602. Phone: 734-763-6384; Fax: 734-763-4782; E-mail: jayhess{at}umich.edu.
Chromosome translocations involving the mixed lineage leukemia gene MLL are associated with aggressive acute leukemias in both children and adults. Leukemogenic MLL fusion proteins delete the MLL SET domain Lys4 methyltransferase activity and fuse MLL to 1 of >40 different translocation partners. Some MLL fusion proteins involve nuclear proteins that are transcriptional activators, whereas others have transcriptional activating activity but instead dimerize the truncated MLL molecule. Both types of MLL fusion proteins enforce persistent expression of Hox a9 and Meis1, which is pivotal for leukemogenesis through mechanisms that remain obscure. Here, we show that nuclear and dimerizable forms of MLL bind with a similar pattern to the Hox a9 locus that overlaps the distribution of wild-type MLL and deregulate transcription of three isoforms of Hox a9. Induction of MLL fusion protein activity is associated with increased levels of histone acetylation and Lys4 methylation at Hox target genes. In addition, the MLL-ENL-ER protein, but not dimerized MLL, also induces dimethylation of histone H3 at Lys79, suggesting alternative mechanisms for transcriptional activation. (Cancer Res 2005; 65(24): 11367-374)
This article has been cited by other articles:
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  A. G. Muntean and J. L. Hess Epigenetic Dysregulation in Cancer Am. J. Pathol., October 1, 2009; 175(4): 1353 - 1361. [Abstract] [Full Text] [PDF]
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 R. K. Slany The molecular biology of mixed lineage leukemia Haematologica, July 1, 2009; 94(7): 984 - 993. [Abstract] [Full Text] [PDF]
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 R. Popovic, L. E. Riesbeck, C. S. Velu, A. Chaubey, J. Zhang, N. J. Achille, F. E. Erfurth, K. Eaton, J. Lu, H. L. Grimes, et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization Blood, April 2, 2009; 113(14): 3314 - 3322. [Abstract] [Full Text] [PDF]
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J. Faber, A. V. Krivtsov, M. C. Stubbs, R. Wright, T. N. Davis, M. van den Heuvel-Eibrink, C. M. Zwaan, A. L. Kung, and S. A. Armstrong HOXA9 is required for survival in human MLL-rearranged acute leukemias Blood, March 12, 2009; 113(11): 2375 - 2385. [Abstract] [Full Text] [PDF]
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 M. G. Guenther, L. N. Lawton, T. Rozovskaia, G. M. Frampton, S. S. Levine, T. L. Volkert, C. M. Croce, T. Nakamura, E. Canaani, and R. A. Young Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia Genes & Dev., December 15, 2008; 22(24): 3403 - 3408. [Abstract] [Full Text] [PDF]
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 J. Lee, P. K. Saha, Q.-H. Yang, S. Lee, J. Y. Park, Y. Suh, S.-K. Lee, L. Chan, R. G. Roeder, and J. W. Lee Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis PNAS, December 9, 2008; 105(49): 19229 - 19234. [Abstract] [Full Text] [PDF]
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D. Mueller, C. Bach, D. Zeisig, M.-P. Garcia-Cuellar, S. Monroe, A. Sreekumar, R. Zhou, A. Nesvizhskii, A. Chinnaiyan, J. L. Hess, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification Blood, December 15, 2007; 110(13): 4445 - 4454. [Abstract] [Full Text] [PDF]
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B. Argiropoulos, E. Yung, and R. K. Humphries Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis Genes & Dev., November 15, 2007; 21(22): 2845 - 2849. [Full Text] [PDF]
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P. Wong, M. Iwasaki, T. C.P. Somervaille, C. W. E. So, and M. L. Cleary Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential Genes & Dev., November 1, 2007; 21(21): 2762 - 2774. [Abstract] [Full Text] [PDF]
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 C. Caslini, Z. Yang, M. El-Osta, T. A. Milne, R. K. Slany, and J. L. Hess Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation Cancer Res., August 1, 2007; 67(15): 7275 - 7283. [Abstract] [Full Text] [PDF]
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 E. Bitoun, P. L. Oliver, and K. E. Davies The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling Hum. Mol. Genet., January 1, 2007; 16(1): 92 - 106. [Abstract] [Full Text] [PDF]
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