11q23 translocations split the "AT-hook" cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. (original) (raw)

• Journal List
• Proc Natl Acad Sci U S A
• v.91(22); 1994 Oct 25
• PMC45071

Proc Natl Acad Sci U S A. 1994 Oct 25; 91(22): 10610–10614.

Department of Medicine, University of Chicago, IL 60637.

Abstract

Translocations involving chromosome band 11q23, found in acute lymphoid and myeloid leukemias, disrupt the MLL gene. This gene encodes a putative transcription factor with homology to the zinc fingers and other domains of the Drosophila trithorax gene product and to the "AT-hook" motif of high mobility group proteins. To map potential transcriptional activation or repression domains of the MLL protein, yeast GAL4 DNA-binding domain and MLL hybrid protein-expressing plasmids were cotransfected with chloramphenicol acetyltransferase reporter plasmids in a transient transfection system. We found that MLL contains a strong activation domain and a repression domain. The former, located telomeric (3') to the breakpoint region, activated transcription 18-fold to > 200-fold, depending on the promoter and cell line used for transfection. A repression domain that repressed transcription 4-fold was located centromeric (5') to the breakpoint region of MLL. The MLL AT-hook domain protein was expressed in bacteria and was utilized in a gel mobility shift assay to assess DNA-binding activity. The MLL AT-hook domain could bind cruciform DNA, recognizing structure rather than sequence of the target DNA. In translocations involving MLL, loss of an activation domain with retention of a repression domain and a DNA-binding domain on the der(11) chromosome could alter the expression of downstream target genes, suggesting a potential mechanism of action for MLL in leukemia.

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• Pedersen-Bjergaard J, Rowley JD. The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood. 1994 May 15;83(10):2780–2786. [PubMed] [Google Scholar]
• Super HJ, McCabe NR, Thirman MJ, Larson RA, Le Beau MM, Pedersen-Bjergaard J, Philip P, Diaz MO, Rowley JD. Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II. Blood. 1993 Dec 15;82(12):3705–3711. [PubMed] [Google Scholar]
• Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R, 3rd, Patel Y, Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10735–10739. [PMC free article] [PubMed] [Google Scholar]
• McCabe NR, Burnett RC, Gill HJ, Thirman MJ, Mbangkollo D, Kipiniak M, van Melle E, Ziemin-van der Poel S, Rowley JD, Diaz MO. Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11794–11798. [PMC free article] [PubMed] [Google Scholar]
• Cimino G, Moir DT, Canaani O, Williams K, Crist WM, Katzav S, Cannizzaro L, Lange B, Nowell PC, Croce CM, et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations. Cancer Res. 1991 Dec 15;51(24):6712–6714. [PubMed] [Google Scholar]
• Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet. 1992 Oct;2(2):113–118. [PubMed] [Google Scholar]
• Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992 Nov 13;71(4):691–700. [PubMed] [Google Scholar]
• Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM, Canaani E. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992 Nov 13;71(4):701–708. [PubMed] [Google Scholar]
• Castelli-Gair JE, García-Bellido A. Interactions of Polycomb and trithorax with cis regulatory regions of Ultrabithorax during the development of Drosophila melanogaster. EMBO J. 1990 Dec;9(13):4267–4275. [PMC free article] [PubMed] [Google Scholar]
• Mazo AM, Huang DH, Mozer BA, Dawid IB. The trithorax gene, a trans-acting regulator of the bithorax complex in Drosophila, encodes a protein with zinc-binding domains. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2112–2116. [PMC free article] [PubMed] [Google Scholar]
• Reeves R, Nissen MS. The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem. 1990 May 25;265(15):8573–8582. [PubMed] [Google Scholar]
• Bianchi ME, Beltrame M, Paonessa G. Specific recognition of cruciform DNA by nuclear protein HMG1. Science. 1989 Feb 24;243(4894 Pt 1):1056–1059. [PubMed] [Google Scholar]
• Rowley JD. The der(11) chromosome contains the critical breakpoint junction in the 4;11, 9;11, and 11;19 translocations in acute leukemia. Genes Chromosomes Cancer. 1992 Oct;5(3):264–266. [PubMed] [Google Scholar]
• Kobayashi H, Espinosa R, 3rd, Thirman MJ, Gill HJ, Fernald AA, Diaz MO, Le Beau MM, Rowley JD. Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization. Blood. 1993 Jul 15;82(2):547–551. [PubMed] [Google Scholar]
• Sadowski I, Ma J, Triezenberg S, Ptashne M. GAL4-VP16 is an unusually potent transcriptional activator. Nature. 1988 Oct 6;335(6190):563–564. [PubMed] [Google Scholar]
• Lillie JW, Green MR. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. [PubMed] [Google Scholar]
• Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. [PubMed] [Google Scholar]
• Gashler AL, Swaminathan S, Sukhatme VP. A novel repression module, an extensive activation domain, and a bipartite nuclear localization signal defined in the immediate-early transcription factor Egr-1. Mol Cell Biol. 1993 Aug;13(8):4556–4571. [PMC free article] [PubMed] [Google Scholar]
• Hakes DJ, Dixon JE. New vectors for high level expression of recombinant proteins in bacteria. Anal Biochem. 1992 May 1;202(2):293–298. [PubMed] [Google Scholar]
• Grieco F, Hay JM, Hull R. An improved procedure for the purification of protein fused with glutathione S-transferase. Biotechniques. 1992 Dec;13(6):856–858. [PubMed] [Google Scholar]
• Bianchi ME. Interaction of a protein from rat liver nuclei with cruciform DNA. EMBO J. 1988 Mar;7(3):843–849. [PMC free article] [PubMed] [Google Scholar]
• Domer PH, Fakharzadeh SS, Chen CS, Jockel J, Johansen L, Silverman GA, Kersey JH, Korsmeyer SJ. Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7884–7888. [PMC free article] [PubMed] [Google Scholar]
• Yamamoto K, Seto M, Akao Y, Iida S, Nakazawa S, Oshimura M, Takahashi T, Ueda R. Gene rearrangement and truncated mRNA in cell lines with 11q23 translocation. Oncogene. 1993 Feb;8(2):479–485. [PubMed] [Google Scholar]
• Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol. 1988 Oct 20;203(4):971–983. [PubMed] [Google Scholar]
• Theill LE, Castrillo JL, Wu D, Karin M. Dissection of functional domains of the pituitary-specific transcription factor GHF-1. Nature. 1989 Dec 21;342(6252):945–948. [PubMed] [Google Scholar]
• Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. [PubMed] [Google Scholar]
• Hahn S. The Yin and the Yang of mammalian transcription. Curr Biol. 1992 Mar;2(3):152–154. [PubMed] [Google Scholar]
• Frisque RJ. Nucleotide sequence of the region encompassing the JC virus origin of DNA replication. J Virol. 1983 Apr;46(1):170–176. [PMC free article] [PubMed] [Google Scholar]
• Oñate SA, Prendergast P, Wagner JP, Nissen M, Reeves R, Pettijohn DE, Edwards DP. The DNA-bending protein HMG-1 enhances progesterone receptor binding to its target DNA sequences. Mol Cell Biol. 1994 May;14(5):3376–3391. [PMC free article] [PubMed] [Google Scholar]
• Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, Sandberg AA, et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med. 1993 Sep 23;329(13):909–914. [PubMed] [Google Scholar]
• Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N, Gale RP, Lange B, Crist WM, Nowell PC, et al. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4631–4635. [PMC free article] [PubMed] [Google Scholar]

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