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Oncogenes, Fusion Genes and Tumor Suppressor Genes

PIG7, transactivated by AML1, promotes apoptosis and differentiation of leukemia cells with AML1–ETO fusion gene

Leukemia volume 26, pages 117–126 (2012)Cite this article

Abstract

AML1, the potent transcription factor in hematopoiesis, is antagonized by AML1–ETO in t(8;21) leukemia. Our previous study showed that the differentiation and apoptosis of Kasumi-1 induced by sodium phenylbutyrate (PB), were accompanied by significant upregulation of PIG7 and AML1b (one of the AML1 isoforms). Here, we further investigated the relationship between AML1b and PIG7, also the effects of PIG7 on leukemia cells. The results demonstrated that exogenous AML1b could upregulate PIG7 expression in HEK-293 and CV-1 cells in sequence-specific and dosage-dependent manners, and this effect was antagonized by AML1–ETO. The specific AML1-binding site required for p53-induced gene 7 (PIG7) transactivation was located between nucleotides −1511 and −1503 in the PIG7 promoter. Overexpression of PIG7 could induce the apoptosis and differentiation of Kasumi-1 and SKNO-1 cells, but showed less effect on NB4 cells directly. Moreover, ectopic expression of PIG7 could sensitize these cell lines to PB or all-trans retinoic acid, respectively, which could then be abrogated by downregulation of PIG7 expression. Furthermore, the primary acute myeloid leukemia cells showed similar response to the ectopic expression of PIG7. In conclusion, PIG7 could be transactivated by AML1, which subsequently induces differentiation and apoptosis of leukemia cells, especially those with AML1–ETO fusion gene.

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References

  1. Basecke J, Feuring-Buske M, Brittinger G, Schaefer UW, Hiddemann W, Griesinger F . Transcription of AML1 in hematopoietic subfractions of normal adults. Ann Hematol 2002; 81: 254–257.

    Article  CAS  Google Scholar 

  2. Downing JR . AML1/CBFbeta transcription complex: its role in normal hematopoiesis and leukemia. Leukemia 2001; 15: 664–665.

    Article  CAS  Google Scholar 

  3. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    Article  CAS  Google Scholar 

  4. Miyoshi H, Ohira M, Shimizu K, Mitani K, Hirai H, Imai T et al. Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res 1995; 23: 2762–2769.

    Article  CAS  Google Scholar 

  5. Meyers S, Lenny N, Hiebert SW . The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol 1995; 15: 1974–1982.

    Article  CAS  Google Scholar 

  6. Tanaka T, Tanaka K, Ogawa S, Kurokawa M, Mitani K, Nishida J et al. An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. EMBO J 1995; 14: 341–350.

    Article  CAS  Google Scholar 

  7. Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN . Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 1997; 89: 349–356.

    Article  CAS  Google Scholar 

  8. Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE . Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 1997; 89: 341–347.

    Article  CAS  Google Scholar 

  9. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA 1998; 95: 10860–10865.

    Article  CAS  Google Scholar 

  10. Asou H, Tashiro S, Hamamoto K, Otsuji A, Kita K, Kamada N . Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991; 77: 2031–2036.

    CAS  Google Scholar 

  11. Wang J, Saunthararajah Y, Redner RL, Liu JM . Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 1999; 59: 2766–2769.

    CAS  PubMed  Google Scholar 

  12. Wang D, Liu J, Tang K, Xu Z, Xiong X, Rao Q et al. Expression of pig7 gene in acute leukemia and its potential to modulate the chemosensitivity of leukemic cells. Leu Res 2009; 33: 28–38.

    Article  CAS  Google Scholar 

  13. Myokai F, Takashiba S, Lebo R, Amar S . A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression: molecular cloning, sequencing, characterization, and chromosomal assignment. Proc Natl Acad Sci USA 1999; 96: 4518–4523.

    Article  CAS  Google Scholar 

  14. Tang X, Molina M, Amar S . p53 short peptide (p53pep164) regulates lipopolysaccharide-induced tumor necrosis factor-alpha factor/cytokine expression. Cancer Res 2007; 67: 1308–1316.

    Article  CAS  Google Scholar 

  15. Hong YH, Lillehoj HS, Lee SH, Park DW, Lillehoj EP . Molecular cloning and characterization of chicken lipopolysaccharide-induced TNF-alpha factor (LITAF). Dev Comp Immunol 30: 919–929.

  16. Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD . The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene 1995; 11: 2667–2674.

    CAS  Google Scholar 

  17. Lenny N, Meyers S, Hiebert SW . Functional domains of the t(8;21) fusion protein, AML-1/ETO. Oncogene 1995; 11: 1761–1769.

    CAS  PubMed  Google Scholar 

  18. Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 1997; 15: 303–306.

    Article  CAS  Google Scholar 

  19. Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 2005; 11: 77–84.

    Article  CAS  Google Scholar 

  20. Minucci S, Nervi C, Lo Coco F, Pelicci PG . Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene 2001; 20: 3110–3115.

    Article  CAS  Google Scholar 

  21. DiGiuseppe JA, Weng LJ, Yu KH, Fu S, Kastan MB, Samid D et al. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. Leukemia 1999; 13: 1243–1253.

    Article  CAS  Google Scholar 

  22. Gore SD, Samid D, Weng LJ . Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res 1997; 3: 1755–1762.

    CAS  PubMed  Google Scholar 

  23. Gore SD, Weng LJ, Zhai S, Figg WD, Donehower RC, Dover GJ et al. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 2001; 7: 2330–2339.

    CAS  PubMed  Google Scholar 

  24. Gore SD, Weng LJ, Figg WD, Zhai S, Donehower RC, Dover G et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 2002; 8: 963–970.

    CAS  PubMed  Google Scholar 

  25. Abba MC, Drake JA, Hawkins KA, Hu Y, Sun H, Notcovich C et al. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression. Breast Cancer Res 2004; 6: R499–R513.

    Article  CAS  Google Scholar 

  26. Kokkinakis DM, Brickner AG, Kirkwood JM, Liu X, Goldwasser JE, Kastrama A et al. Mitotic arrest, apoptosis, and sensitization to chemotherapy of melanomas by methionine deprivation stress. Mol Cancer Res 2006; 4: 575–589.

    Article  CAS  Google Scholar 

  27. Matsumura Y, Matsumura Y, Nishigori C, Horio T, Miyachi Y . PIG7/LITAF gene mutation and overexpression of its gene product in extramammary Paget's disease. Int J Cancer 2004; 111: 218–223.

    Article  CAS  Google Scholar 

  28. Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 2007; 109: 271–280.

    Article  CAS  Google Scholar 

  29. Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L et al. Large-scale cDNA transfection screening for genes related to cancer development and progression. Proc Natl Acad Sci USA 2004; 101: 15724–15729.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to kind assistance from the technicians in Flow Cytometry Core and Instrument Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. This work was supported by the National Natural Science Foundation of China (30971290), National Basic Research Program of China (2011CB964801), Special Scientific Fund for Public Welfare Health Industry (201002024) and National Science and Technology Major Project (2011ZX09302-007-04)

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  1. J Liu

    Present address: 3Current address: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China,

  2. J Liu and H Xing: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    J Liu, H Xing, Y Chen, L Wang, D Wang, Q Rao, K Tang, Z Tian, K He, M Wang & J Wang

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Correspondence to M Wang or J Wang.

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Liu, J., Xing, H., Chen, Y. et al. PIG7, transactivated by AML1, promotes apoptosis and differentiation of leukemia cells with AML1–ETO fusion gene. Leukemia 26, 117–126 (2012). https://doi.org/10.1038/leu.2011.178

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