Abstract
Acute myeloid leukaemia (AMI) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells1,2. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40% of patients with the M2 subtype of AMI disrupts both the AML1 (CBFA2) gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8 (refs 3–5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DMA-binding domain, fused to most of ETO, a protein of unknown function. We generated mice that mimic human t(8;21) with a ‘knock-in’ strategy. Mice heterozygous for an AML1–ETO allele (AML1–ETO/+) die in midgestation from haemorrhaging in the central nervous system and exhibit a severe block in fetal liver haematopoiesis. This phenotype is very similar to that resulting from homozygous disruption of the AML1 (Cbfa2) or Cbfb genes6–8, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AMU-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CPU) assays, unlike Cbfa2−/− or Cbfb−/− cells, which form no colonies in vitro6,8. This indicates that AML1–ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.
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References
Rowley, J.D. Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res. 44, 3159–3168 (1984).
Bitter, M.A. et al. Associations between morphology, karyotype, and clinical features in myeloid leukemias. Hum. Pathol. 18, 211–225 (1987).
Miyoshi, H. et al. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc. Natl. Acad. Sci. USA 88, 10431–10434 (1991).
Erickson, P. et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 80, 1825–1831 (1992).
Nisson, P.E. Watkins, P.C. & Sacchi, N. Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. Cancer Genet. Cytogenet. 63, 81–88 (1992).
Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoesis. Proc. Natl. Acad. Sd. USA 93, 3444–3449 (1996).
Okuda, T. van Deursen, J. Hiebert, S.W. Grosveld, G. & Downing, J.R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996).
Wang, Q. et al. The core-binding factor (CBF) subunit is essential for CBF12 (AML1) function in vivo. Cell 87, 697–708 (1996).
Miyoshi, H. et al. The t(8-21) Translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J. 12, 2715–2721 (1993).
Capecchi, M.R. Altering the genome by homologous recombination. Science 244, 1288–1292 (1989).
Williams, B.O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13, 4251–4259 (1994).
Erickson, P.F. et al. ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: Implications for t(8;21) leukemogenesis and monitoring residual disease. Blood 88, 1813–1823 (1996).
Meyers, S. Lenny, N. Sun, W. & Hiebert, S.W. AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia. Oncogene 13, 303–312 (1996).
Gottschalk, L.R. & Leiden, J.M. Identification and functional characterization of the human T-cell receptor beta gene transcriptional enhancer: common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor alpha and beta genes. Mol. Cell. Biol. 10, 5486–5495 (1990).
Frank, R. et al. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene 11, 2667–2674 (1995).
Hsiang, Y.H. Spencer, D. Wang, S. Speck, N.A. & Raulet, D.H. The role of viral enhancer “core” motif-related sequences in regulating T cell receptor-gamma and -delta gene expression. J. Immunol. 150, 3905–3916 (1993).
Cameron, S. Taylor, D.S. Tepas, E.C. Speck, N.A. & Mathey-Prevot, B. Identification of a critical regulatory site in the human interleukin–3 promoter by in vivo footprinting. Blood 83, 2851–2859 (1994).
Suzow, J. & Friedman, A.D. The murine myeloperoxidase promoter contains several functional elements, one of which binds a cell type-restricted transcription factor, myeloid nuclear factor 1 (MyNF1). Mol. Cell. Biol. 13, 2141–2151 (1993).
Nuchprayoon, I. et al. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2beta/CBFbeta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol. Cell. Biol. 14, 5558–5568 (1994).
Zhang, D.E. et al. Identification of a region which directs monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1). Mol. Cell. Biol. 14, 8085–8095 (1994).
Wotton, D. Ghysdael, J. Wang, S. Speck, N.A. & Owen, M.J. Cooperative binding of Ets-1 and core binding factor to DNA. Mol. Cell. Biol. 14, 840–850 (1994).
Giese, K. Kingsley, C. Kirshner, J.R. & Grosschedl, R. Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1–induced DNA bending and multiple protein-protein interactions. Genes Dev. 9, 995–1008 (1995).
Armesilla, A.L. Calvo, D. & Vega, M.A. Structural and functional characterization of the Human CD36 gene promoter. J. Biol. Chem. 271, 7781–7787 (1996).
Meyers, S. Lenny, N. & Hiebert, S.W. The t(8:21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol. Cell. Biol. 15, 1974–1982 (1995).
Rhoades, K.L. et al. Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis. Proc. Natl. Acad. Sci. USA 93, 11895–11900 (1996).
Haas, J.G. et al. Constitutive monocyte-restricted activity of NF-M, a nuclear factor that binds to a OEBP motif. J. Immunol. 149, 237–243 (1992).
Liu, P. et al. Fusion between transcription factor CBFB/PEBP26 and a myosin heavy chain in acute myeloid leukemia. Science 261, 1041–1044 (1993).
Castilla, L.H. et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 87, 687–696 (1996).
Li, E. Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Tsai, F.Y. et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371, 221–226 (1994).
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Yergeau, D., Hetherington, C., Wang, Q. et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 15, 303–306 (1997). https://doi.org/10.1038/ng0397-303
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DOI: https://doi.org/10.1038/ng0397-303
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