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Overexpression of amyloid precursor protein in acute myeloid leukemia enhances extramedullary infiltration by MMP-2

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Tumor Biology

Abstract

It is known that leukemia patients with extramedullary infiltration (EMI) have a worse prognosis than patients without it. Recent data indicate that the amyloid precursor protein (APP) is involved in cell adhesion, motility, and proliferation. The expression of APP and its prognostic significance in acute myeloid leukemia (AML) have not been studied. Our study shows that AML/ETO+ leukemia patients that overexpress APP easily get EMI and that their long-term survival rate is lower than patients without overexpression of APP. In an in vitro study, we knocked down APP in Kasumi-1 cells using small interfering RNA (siRNA). Transwell data show that siRNA/APP substantially impairs cell migration, but it does not inhibit cell proliferation. Furthermore, by quantitative real-time polymerase chain reaction and Western blot, we found that siRNA/APP decreases MMP-2 expression in vitro. Our study provides a novel clue that APP is involved in the extramedullary infiltration of leukemia by MMP-2.

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References

  1. Cornell RF, Palmer J. Adult acute leukemia. Disease-a-month: DM. 2012;58:219–38.

    Article  PubMed  Google Scholar 

  2. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from cancer and leukemia group B. Blood. 2002;100:4325–36.

    Article  PubMed  CAS  Google Scholar 

  3. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–83.

    PubMed  CAS  Google Scholar 

  4. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92:2322–33.

    PubMed  CAS  Google Scholar 

  5. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–5.

    Article  PubMed  CAS  Google Scholar 

  6. Robakis NK, Wisniewski HM, Jenkins EC, Devine-Gage EA, Houck GE, Yao XL, et al. Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome. Lancet. 1987;1:384–5.

    Article  PubMed  CAS  Google Scholar 

  7. Torroja L, Packard M, Gorczyca M, White K, Budnik V. The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J Neurosci. 1999;19:7793–803.

    PubMed  CAS  Google Scholar 

  8. Yang G, Gong YD, Gong K, Jiang WL, Kwon E, Wang P, et al. Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett. 2005;384:66–71.

    Article  PubMed  CAS  Google Scholar 

  9. Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid. Mol Neurodegener. 2006;1:5.

    Article  PubMed  Google Scholar 

  10. Muller T, Meyer HE, Egensperger R, Marcus K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease. Prog Neurobiol. 2008;85:393–406.

    Article  PubMed  Google Scholar 

  11. Nakagawa T, Kabuto M, Kubota T, Kodera T, Sato K. Production of amyloid beta protein precursor as a proteinase inhibitor by human astrocytic tumors. Anticancer Res. 1999;19:2963–8.

    PubMed  CAS  Google Scholar 

  12. Meng JY, Kataoka H, Itoh H, Koono M. Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer. 2001;92:31–9.

    Article  PubMed  CAS  Google Scholar 

  13. Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A. Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res. 2003;63:7032–7.

    PubMed  CAS  Google Scholar 

  14. Ko SY, Lin SC, Chang KW, Wong YK, Liu CJ, Chi CW, et al. Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer. 2004;111:727–32.

    Article  PubMed  CAS  Google Scholar 

  15. Krause K, Karger S, Sheu SY, Aigner T, Kursawe R, Gimm O, et al. Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis. J Endocrinol. 2008;198:291–9.

    Article  PubMed  CAS  Google Scholar 

  16. Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, et al. Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res. 2009;69:137–42.

    Article  PubMed  CAS  Google Scholar 

  17. Baldus CD, Liyanarachchi S, Mrozek K, Auer H, Tanner SM, Guimond M, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101:3915–20.

    Article  PubMed  CAS  Google Scholar 

  18. Klein G, Vellenga E, Fraaije MW, Kamps WA, de Bont ES. The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Crit Rev Oncol Hematol. 2004;50:87–100.

    Article  PubMed  CAS  Google Scholar 

  19. Lin LI, Lin DT, Chang CJ, Lee CY, Tang JL, et al. Marrow matrix metalloproteinases (MMPs) and tissue inhibitors of MMP in acute leukaemia: potential role of MMP-9 as a surrogate marker to monitor leukaemic status in patients with acute myelogenous leukaemia. Br J Haematol. 2002;117:835–41.

    Article  PubMed  CAS  Google Scholar 

  20. Suminoe A, Matsuzaki A, Hattori H, Koga Y, Ishii E. Expression of matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) genes in blasts of infant acute lymphoblastic leukemia with organ involvement. Leuk Res. 2007;31:1437–40.

    Article  PubMed  CAS  Google Scholar 

  21. Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U, et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia. 2002;16:53–9.

    Article  PubMed  CAS  Google Scholar 

  22. An International System for Human Cytogenetic Nomenclature (1985) ISCN 1985. Report of the Standing Committee on Human Cytogenetic Nomenclature. Birth Defects Orig Artic Ser. 1985;21:1–117.

    Google Scholar 

  23. Federico M. From lentiviruses to lentivirus vectors. Methods Mol Biol. 2003;229:3–15.

    PubMed  CAS  Google Scholar 

  24. Tiscornia G, Singer O, Verma IM. Production and purification of lentiviral vectors. Nat Protoc. 2006;1:241–5.

    Article  PubMed  CAS  Google Scholar 

  25. Sena-Esteves M, Tebbets JC, Steffens S, Crombleholme T, Flake AW. Optimized large-scale production of high titer lentivirus vector pseudotypes. J Virol Methods. 2004;122:131–9.

    Article  PubMed  CAS  Google Scholar 

  26. Janowska-Wieczorek A, Marquez LA, Matsuzaki A, Hashmi HR, Larratt LM, Boshkov LM, et al. Expression of matrix metalloproteinases (MMP-2 and −9) and tissue inhibitors of metalloproteinases (TIMP-1 and −2) in acute myelogenous leukaemia blasts: comparison with normal bone marrow cells. Br J Haematol. 1999;105:402–11.

    Article  PubMed  CAS  Google Scholar 

  27. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.

    Article  PubMed  CAS  Google Scholar 

  28. Itoh Y, Takamura A, Ito N, Maru Y, Sato H, Suenaga N, et al. Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. EMBO J. 2001;20:4782–93.

    Article  PubMed  CAS  Google Scholar 

  29. Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999;13:781–92.

    PubMed  CAS  Google Scholar 

  30. Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, et al. Matrix metalloproteinase-2 and −9 secreted by leukemic cells increase the permeability of blood–brain barrier by disrupting tight junction proteins. PLoS One. 2011;6:e20599.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Ling Jiang, Guopan Yu, Zhixiang Wang & Fanyi Meng

  2. Institute of Genetic Engineering, Southern Medical University, Guangzhou, China

    Wei Meng & Wenli Ma

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  1. Ling Jiang
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  2. Guopan Yu
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  3. Wei Meng
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  4. Zhixiang Wang
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  5. Fanyi Meng
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  6. Wenli Ma
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Correspondence to Fanyi Meng or Wenli Ma.

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Jiang, L., Yu, G., Meng, W. et al. Overexpression of amyloid precursor protein in acute myeloid leukemia enhances extramedullary infiltration by MMP-2. Tumor Biol. 34, 629–636 (2013). https://doi.org/10.1007/s13277-012-0589-7

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  • DOI: https://doi.org/10.1007/s13277-012-0589-7

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