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. 1996 Oct 15;93(21):11895–11900. doi: 10.1073/pnas.93.21.11895

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.

K L Rhoades 1, C J Hetherington 1, J D Rowley 1, S W Hiebert 1, G Nucifora 1, D G Tenen 1, D E Zhang 1
PMCID: PMC38155  PMID: 8876234

Abstract

AML1 is involved in the (8;21) translocation, associated with acute myelogenous leukemia (AML)-type M2, which results in the production of the AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by which AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colony-stimulating factor promoter. Herein, we explored the effect of AML1-ETO on regulation of a myeloid-specific AML1 target, the macrophage colony-stimulating factor (M-CSF) receptor promoter. We found that AML1-ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AML1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls. The upregulation of M-CSF receptor expression by AML1-ETO may contribute to the development of a leukemic state in these patients.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bae S. C., Yamaguchi-Iwai Y., Ogawa E., Maruyama M., Inuzuka M., Kagoshima H., Shigesada K., Satake M., Ito Y. Isolation of PEBP2 alpha B cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1. Oncogene. 1993 Mar;8(3):809–814. [PubMed] [Google Scholar]
  2. Borycki A. G., Foucrier J., Saffar L., Leibovitch S. A. Repression of the CSF-1 receptor (c-fms proto-oncogene product) by antisense transfection induces G1-growth arrest in L6 alpha 1 rat myoblasts. Oncogene. 1995 May 4;10(9):1799–1811. [PubMed] [Google Scholar]
  3. Bourette R. P., Myles G. M., Carlberg K., Chen A. R., Rohrschneider L. R. Uncoupling of the proliferation and differentiation signals mediated by the murine macrophage colony-stimulating factor receptor expressed in myeloid FDC-P1 cells. Cell Growth Differ. 1995 Jun;6(6):631–645. [PubMed] [Google Scholar]
  4. 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. 1994 May 15;83(10):2851–2859. [PubMed] [Google Scholar]
  5. Coussens L., Van Beveren C., Smith D., Chen E., Mitchell R. L., Isacke C. M., Verma I. M., Ullrich A. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature. 1986 Mar 20;320(6059):277–280. doi: 10.1038/320277a0. [DOI] [PubMed] [Google Scholar]
  6. Era T., Asou N., Yamaguchi K., Yamasaki H., Kamada N., Nishikawa S., Takatsuki K. Expression of AML1 and ETO Transcripts in hematopoietic cells. Leukemia. 1995 Oct;9 (Suppl 1):S26–S28. [PubMed] [Google Scholar]
  7. Erickson P. F., Robinson M., Owens G., Drabkin H. A. The ETO portion of acute myeloid leukemia t(8;21) fusion transcript encodes a highly evolutionarily conserved, putative transcription factor. Cancer Res. 1994 Apr 1;54(7):1782–1786. [PubMed] [Google Scholar]
  8. Erickson P., Gao J., Chang K. S., Look T., Whisenant E., Raimondi S., Lasher R., Trujillo J., Rowley J., Drabkin H. 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. 1992 Oct 1;80(7):1825–1831. [PubMed] [Google Scholar]
  9. Feinstein P. G., Kornfeld K., Hogness D. S., Mann R. S. Identification of homeotic target genes in Drosophila melanogaster including nervy, a proto-oncogene homologue. Genetics. 1995 Jun;140(2):573–586. doi: 10.1093/genetics/140.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Frank R., Zhang J., Uchida H., Meyers S., Hiebert S. W., Nimer S. D. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene. 1995 Dec 21;11(12):2667–2674. [PubMed] [Google Scholar]
  11. Gisselbrecht S., Fichelson S., Sola B., Bordereaux D., Hampe A., André C., Galibert F., Tambourin P. Frequent c-fms activation by proviral insertion in mouse myeloblastic leukaemias. Nature. 1987 Sep 17;329(6136):259–261. doi: 10.1038/329259a0. [DOI] [PubMed] [Google Scholar]
  12. Golub T. R., Barker G. F., Bohlander S. K., Hiebert S. W., Ward D. C., Bray-Ward P., Morgan E., Raimondi S. C., Rowley J. D., Gilliland D. G. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4917–4921. doi: 10.1073/pnas.92.11.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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. 1990 Oct;10(10):5486–5495. doi: 10.1128/mcb.10.10.5486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hiebert S. W., Sun W., Davis J. N., Golub T., Shurtleff S., Buijs A., Downing J. R., Grosveld G., Roussell M. F., Gilliland D. G. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol. 1996 Apr;16(4):1349–1355. doi: 10.1128/mcb.16.4.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hoey T., Weinzierl R. O., Gill G., Chen J. L., Dynlacht B. D., Tjian R. Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators. Cell. 1993 Jan 29;72(2):247–260. doi: 10.1016/0092-8674(93)90664-c. [DOI] [PubMed] [Google Scholar]
  16. Kania M. A., Bonner A. S., Duffy J. B., Gergen J. P. The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system. Genes Dev. 1990 Oct;4(10):1701–1713. doi: 10.1101/gad.4.10.1701. [DOI] [PubMed] [Google Scholar]
  17. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  18. Lenny N., Meyers S., Hiebert S. W. Functional domains of the t(8;21) fusion protein, AML-1/ETO. Oncogene. 1995 Nov 2;11(9):1761–1769. [PubMed] [Google Scholar]
  19. Levanon D., Negreanu V., Bernstein Y., Bar-Am I., Avivi L., Groner Y. AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization. Genomics. 1994 Sep 15;23(2):425–432. doi: 10.1006/geno.1994.1519. [DOI] [PubMed] [Google Scholar]
  20. Matsushime H., Roussel M. F., Ashmun R. A., Sherr C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. doi: 10.1016/0092-8674(91)90101-4. [DOI] [PubMed] [Google Scholar]
  21. Meyers S., Downing J. R., Hiebert S. W. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol. 1993 Oct;13(10):6336–6345. doi: 10.1128/mcb.13.10.6336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Meyers S., Lenny N., Hiebert S. W. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995 Apr;15(4):1974–1982. doi: 10.1128/mcb.15.4.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miyoshi H., Kozu T., Shimizu K., Enomoto K., Maseki N., Kaneko Y., Kamada N., Ohki M. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J. 1993 Jul;12(7):2715–2721. doi: 10.1002/j.1460-2075.1993.tb05933.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miyoshi H., Ohira M., Shimizu K., Mitani K., Hirai H., Imai T., Yokoyama K., Soeda E., Ohki M. Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res. 1995 Jul 25;23(14):2762–2769. doi: 10.1093/nar/23.14.2762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miyoshi H., Shimizu K., Kozu T., Maseki N., Kaneko Y., Ohki M. 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 U S A. 1991 Dec 1;88(23):10431–10434. doi: 10.1073/pnas.88.23.10431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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. 1992 Oct 15;63(2):81–88. doi: 10.1016/0165-4608(92)90384-k. [DOI] [PubMed] [Google Scholar]
  27. Nuchprayoon I., Meyers S., Scott L. M., Suzow J., Hiebert S., Friedman A. D. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol. 1994 Aug;14(8):5558–5568. doi: 10.1128/mcb.14.8.5558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nucifora G., Birn D. J., Espinosa R., 3rd, Erickson P., LeBeau M. M., Roulston D., McKeithan T. W., Drabkin H., Rowley J. D. Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood. 1993 May 15;81(10):2728–2734. [PubMed] [Google Scholar]
  29. Nucifora G., Rowley J. D. The AML1 and ETO genes in acute myeloid leukemia with a t(8;21). Leuk Lymphoma. 1994 Aug;14(5-6):353–362. doi: 10.3109/10428199409049690. [DOI] [PubMed] [Google Scholar]
  30. Ogawa E., Maruyama M., Kagoshima H., Inuzuka M., Lu J., Satake M., Shigesada K., Ito Y. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6859–6863. doi: 10.1073/pnas.90.14.6859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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. 1996 Jan 26;84(2):321–330. doi: 10.1016/s0092-8674(00)80986-1. [DOI] [PubMed] [Google Scholar]
  32. Panterne B., Zhou Y. Q., Hatzfeld J., Li M. L., Levesque J. P., Clark S. C., Hatzfeld A. CSF-1 control of C-FMS expression in normal human bone marrow progenitors. J Cell Physiol. 1993 May;155(2):282–289. doi: 10.1002/jcp.1041550209. [DOI] [PubMed] [Google Scholar]
  33. Pharr P. N., Ogawa M., Hofbauer A., Longmore G. D. Expression of an activated erythropoietin or a colony-stimulating factor 1 receptor by pluripotent progenitors enhances colony formation but does not induce differentiation. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7482–7486. doi: 10.1073/pnas.91.16.7482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Prosser H. M., Wotton D., Gegonne A., Ghysdael J., Wang S., Speck N. A., Owen M. J. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9934–9938. doi: 10.1073/pnas.89.20.9934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Redondo J. M., Pfohl J. L., Hernandez-Munain C., Wang S., Speck N. A., Krangel M. S. Indistinguishable nuclear factor binding to functional core sites of the T-cell receptor delta and murine leukemia virus enhancers. Mol Cell Biol. 1992 Nov;12(11):4817–4823. doi: 10.1128/mcb.12.11.4817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Regenstreif L. J., Rossant J. Expression of the c-fms proto-oncogene and of the cytokine, CSF-1, during mouse embryogenesis. Dev Biol. 1989 May;133(1):284–294. doi: 10.1016/0012-1606(89)90319-9. [DOI] [PubMed] [Google Scholar]
  37. Rettenmier C. W., Sacca R., Furman W. L., Roussel M. F., Holt J. T., Nienhuis A. W., Stanley E. R., Sherr C. J. Expression of the human c-fms proto-oncogene product (colony-stimulating factor-1 receptor) on peripheral blood mononuclear cells and choriocarcinoma cell lines. J Clin Invest. 1986 Jun;77(6):1740–1746. doi: 10.1172/JCI112496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rhoades K. L., Golub S. H., Economou J. S. The regulation of the human tumor necrosis factor alpha promoter region in macrophage, T cell, and B cell lines. J Biol Chem. 1992 Nov 5;267(31):22102–22107. [PubMed] [Google Scholar]
  39. Roberts W. M., Shapiro L. H., Ashmun R. A., Look A. T. Transcription of the human colony-stimulating factor-1 receptor gene is regulated by separate tissue-specific promoters. Blood. 1992 Feb 1;79(3):586–593. [PubMed] [Google Scholar]
  40. Ross I. L., Dunn T. L., Yue X., Roy S., Barnett C. J., Hume D. A. Comparison of the expression and function of the transcription factor PU.1 (Spi-1 proto-oncogene) between murine macrophages and B lymphocytes. Oncogene. 1994 Jan;9(1):121–132. [PubMed] [Google Scholar]
  41. Roussel M. F., Dull T. J., Rettenmier C. W., Ralph P., Ullrich A., Sherr C. J. Transforming potential of the c-fms proto-oncogene (CSF-1 receptor). Nature. 1987 Feb 5;325(6104):549–552. doi: 10.1038/325549a0. [DOI] [PubMed] [Google Scholar]
  42. Rowley J. D. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet. 1973 Jun;16(2):109–112. [PubMed] [Google Scholar]
  43. Sariban E., Mitchell T., Kufe D. Expression of the c-fms proto-oncogene during human monocytic differentiation. Nature. 1985 Jul 4;316(6023):64–66. doi: 10.1038/316064a0. [DOI] [PubMed] [Google Scholar]
  44. Scott L. M., Civin C. I., Rorth P., Friedman A. D. A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood. 1992 Oct 1;80(7):1725–1735. [PubMed] [Google Scholar]
  45. Sherr C. J. Colony-stimulating factor-1 receptor. Blood. 1990 Jan 1;75(1):1–12. [PubMed] [Google Scholar]
  46. Sherr C. J., Rettenmier C. W., Sacca R., Roussel M. F., Look A. T., Stanley E. R. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell. 1985 Jul;41(3):665–676. doi: 10.1016/s0092-8674(85)80047-7. [DOI] [PubMed] [Google Scholar]
  47. Stanley E. R., Guilbert L. J., Tushinski R. J., Bartelmez S. H. CSF-1--a mononuclear phagocyte lineage-specific hemopoietic growth factor. J Cell Biochem. 1983;21(2):151–159. doi: 10.1002/jcb.240210206. [DOI] [PubMed] [Google Scholar]
  48. Sun W., Graves B. J., Speck N. A. Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins. J Virol. 1995 Aug;69(8):4941–4949. doi: 10.1128/jvi.69.8.4941-4949.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Takahashi A., Satake M., Yamaguchi-Iwai Y., Bae S. C., Lu J., Maruyama M., Zhang Y. W., Oka H., Arai N., Arai K. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood. 1995 Jul 15;86(2):607–616. [PubMed] [Google Scholar]
  50. Visvader J., Verma I. M. Differential transcription of exon 1 of the human c-fms gene in placental trophoblasts and monocytes. Mol Cell Biol. 1989 Mar;9(3):1336–1341. doi: 10.1128/mcb.9.3.1336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Voso M. T., Burn T. C., Wulf G., Lim B., Leone G., Tenen D. G. Inhibition of hematopoiesis by competitive binding of transcription factor PU.1. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):7932–7936. doi: 10.1073/pnas.91.17.7932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wang Q., Stacy T., Binder M., Marin-Padilla M., Sharpe A. H., Speck N. A. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444–3449. doi: 10.1073/pnas.93.8.3444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wang S., Wang Q., Crute B. E., Melnikova I. N., Keller S. R., Speck N. A. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol Cell Biol. 1993 Jun;13(6):3324–3339. doi: 10.1128/mcb.13.6.3324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wiktor-Jedrzejczak W., Bartocci A., Ferrante A. W., Jr, Ahmed-Ansari A., Sell K. W., Pollard J. W., Stanley E. R. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4828–4832. doi: 10.1073/pnas.87.12.4828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wiktor-Jedrzejczak W., Ratajczak M. Z., Ptasznik A., Sell K. W., Ahmed-Ansari A., Ostertag W. CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages. Exp Hematol. 1992 Sep;20(8):1004–1010. [PubMed] [Google Scholar]
  56. Wolin M., Kornuc M., Hong C., Shin S. K., Lee F., Lau R., Nimer S. Differential effect of HTLV infection and HTLV Tax on interleukin 3 expression. Oncogene. 1993 Jul;8(7):1905–1911. [PubMed] [Google Scholar]
  57. Zhang D. E., Fujioka K., Hetherington C. J., Shapiro L. H., Chen H. M., Look A. T., Tenen D. G. Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1). Mol Cell Biol. 1994 Dec;14(12):8085–8095. doi: 10.1128/mcb.14.12.8085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Zhang D. E., Hetherington C. J., Chen H. M., Tenen D. G. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol. 1994 Jan;14(1):373–381. doi: 10.1128/mcb.14.1.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Zhang D. E., Hetherington C. J., Meyers S., Rhoades K. L., Larson C. J., Chen H. M., Hiebert S. W., Tenen D. G. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol Cell Biol. 1996 Mar;16(3):1231–1240. doi: 10.1128/mcb.16.3.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Zhu X., Yeadon J. E., Burden S. J. AML1 is expressed in skeletal muscle and is regulated by innervation. Mol Cell Biol. 1994 Dec;14(12):8051–8057. doi: 10.1128/mcb.14.12.8051. [DOI] [PMC free article] [PubMed] [Google Scholar]

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