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Human AML cells in NOD/SCID mice: engraftment potential and gene expression

Leukemia volume 16, pages 1818–1826 (2002)Cite this article

Abstract

Most cases of human acute myeloid leukemia (AML) engraft in irradiated non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Intravenous transfer of as few as 105 human AML cells resulted in engraftment. Cases with poor prognosis clinical features, including FLT3 mutations, tended to engraft efficiently. Nevertheless, AML cells obtained from patients at relapse did not engraft more efficiently than cells obtained from the same patients at initial diagnosis. One passage of human AML cells in NOD/SCID mice did not appear to select for increased virulence, as measured by serial transplantation efficiency. Finally, cDNA microarray analyses indicated that ∼95% of genes were expressed at similar levels in human AML cells immunopurified after growth in mice, as compared to cells assessed directly from patients. Thus, the growth of human AML cells in NOD/SCID mice could yield large numbers of human AML cells for direct experimental use and could also function as a renewable, potentially unlimited source of leukemia cells, via serial transplantation.

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References

  1. Brendel C, Neubauer A . Characteristics and analysis of normal and leukemic stem cells: current concepts and future directions Leukemia 2000 14: 1711–1717

    Article  CAS  PubMed  Google Scholar 

  2. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell Nat Med 1997 3: 730–737

    Article  CAS  PubMed  Google Scholar 

  3. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE . A cell initiating human acute myeloid leukaemia after transplantation into SCID mice Nature 1994 367: 645–648

    Article  CAS  PubMed  Google Scholar 

  4. Dick JE, Bhatia M, Gan O, Kapp U, Wang JC . Assay of human stem cells by repopulation of NOD/SCID mice Stem Cells 1997 15 (Suppl. 1): 199–203 discussion 204–207

    Article  Google Scholar 

  5. McCulloch EA . Toward a leukemia treatment strategy based on the probability of stem cell death: an essay in honor of Dr Emil J Freireich Clin Cancer Res 1997 3: 2676–2681

    CAS  PubMed  Google Scholar 

  6. Namikawa R, Ueda R, Kyoizumi S . Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice Blood 1993 82: 2526–2536

    CAS  PubMed  Google Scholar 

  7. Terpstra W, Prins A, Visser T, Wognum B, Wagemaker G, Lowenberg B, Wielenga J . Conditions for engraftment of human acute myeloid leukemia (AML) in SCID mice Leukemia 1995 9: 1573–1577

    CAS  PubMed  Google Scholar 

  8. Cesano A, Hoxie JA, Lange B, Nowell PC, Bishop J, Santoli D . The severe combined immunodeficient (SCID) mouse as a model for human myeloid leukemias Oncogene 1992 7: 827–836

    CAS  PubMed  Google Scholar 

  9. Sawyers CL, Gishizky ML, Quan S, Golde DW, Witte ON . Propagation of human blastic myeloid leukemias in the SCID mouse Blood 1992 79: 2089–2098

    CAS  PubMed  Google Scholar 

  10. Dick JE . Human stem cell assays in immune-deficient mice Curr Opin Hematol 1996 3: 405–409

    Article  CAS  PubMed  Google Scholar 

  11. Lapidot T, Fajerman Y, Kollet O . Immune-deficient SCID and NOD/SCID mice models as functional assays for studying normal and malignant human hematopoiesis J Mol Med 1997 75: 664–673

    Article  CAS  PubMed  Google Scholar 

  12. Rombouts WJ, Martens AC, Ploemacher RE . Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model Leukemia 2000 14: 889–897

    Article  CAS  PubMed  Google Scholar 

  13. Ailles LE, Gerhard B, Kawagoe H, Hogge DE . Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice Blood 1999 94: 1761–1772

    CAS  PubMed  Google Scholar 

  14. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group Ann Intern Med 1985 103: 620–625

    Article  CAS  PubMed  Google Scholar 

  15. Blair A, Hogge DE, Sutherland HJ . Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR Blood 1998 92: 4325–4335

    CAS  PubMed  Google Scholar 

  16. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S . Internal tandem duplication of the flt3 gene found in acute myeloid leukemia Leukemia 1996 10: 1911–1918

    CAS  PubMed  Google Scholar 

  17. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T . Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies Blood 2001 97: 2434–2439

    Article  CAS  PubMed  Google Scholar 

  18. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE . Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene Leukemia 2000 14: 675–683

    Article  CAS  PubMed  Google Scholar 

  19. Kondo M, Horibe K, Takahashi Y, Matsumoto K, Fukuda M, Inaba J, Kato K, Kojima S, Matsuyama T . Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia Med Pediatr Oncol 1999 33: 525–529

    Article  CAS  PubMed  Google Scholar 

  20. Civin CI . Human monomyeloid cell membrane antigens Exp Hematol 1990 18: 461–467

    CAS  PubMed  Google Scholar 

  21. Trischmann TM, Schepers KG, Civin CI . Measurement of CD34+ cells in bone marrow by flow cytometry J Hematother 1993 2: 305–313

    Article  CAS  PubMed  Google Scholar 

  22. Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM, Civin CI . STK–1 the human homolog of FLK2/FLT3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells Proc Natl Acad Sci USA 1994 91: 459–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, Chen Y, Su YA, Trent JM . Use of a cDNA microarray to analyse gene expression patterns in human cancer Nat Genet 1996 14: 457–460

    Article  CAS  PubMed  Google Scholar 

  24. Khan J, Simon R, Bittner M, Chen Y, Leighton SB, Pohida T, Smith PD, Jiang Y, Gooden GC, Trent JM, Meltzer PS . Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays Cancer Res 1998 58: 5009–5013

    CAS  PubMed  Google Scholar 

  25. Chen Y, Dougherty ER, Bittner ML . Ratio based decisions and the quantitative analysis of cDNA microarray images Biomed Opt 1997 2: 364–374

    Article  CAS  Google Scholar 

  26. Kruskal WH . Use of ranks in one criterian variance analysis J Am Stat Assoc 1965 47: M583–621

    Article  Google Scholar 

  27. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L . The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1 Blood 1998 91: 4523–4530

    CAS  PubMed  Google Scholar 

  28. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T . Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4 Science 1999 283: 845–848

    Article  CAS  PubMed  Google Scholar 

  29. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T . Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product Leukemia 1998 12: 1333–1337

    Article  CAS  PubMed  Google Scholar 

  30. Tse KF, Mukherjee G, Small D . Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation Leukemia 2000 14: 1766–1776

    Article  CAS  PubMed  Google Scholar 

  31. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, Bernstein ID, Radich JP . Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia Blood 2001 97: 89–94

    Article  CAS  PubMed  Google Scholar 

  32. Kamel-Reid S, Letarte M, Doedens M, Greaves A, Murdoch B, Grunberger T, Lapidot T, Thorner P, Freedman MH, Phillips RA . Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice Blood 1991 78: 2973–2981

    CAS  PubMed  Google Scholar 

  33. Yang Y, Britos-Bray M, Cheng L, Civin CI, Friedman AD . Mutations which accelerate G1 cooperate with CBFb-SMMHC to induce acute leukemia in mice Blood 2000 96: 386a

    Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health Grant P01CA70970.

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Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R Lumkul, N-C Gorin, MT Malehorn, GT Hoehn, R Zheng, B Baldwin, D Small, S Gore, D Smith & CI Civin

  2. Department of Hematology, Hospital Saint-Antoine, Paris, France

    N-C Gorin

  3. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    PS Meltzer

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Lumkul, R., Gorin, NC., Malehorn, M. et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia 16, 1818–1826 (2002). https://doi.org/10.1038/sj.leu.2402632

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