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Animal Models

A robust xenotransplantation model for acute myeloid leukemia

Abstract

Xenotransplantation of human acute myeloid leukemia (AML) in immunocompromised animals has been critical for defining leukemic stem cells. However, existing immunodeficient strains of mice have short life spans and low levels of AML cell engraftment, hindering long-term evaluation of primary human AML biology. A recent study suggested that NOD/LtSz-scid IL2Rγc null (NSG) mice have enhanced AML cell engraftment, but this relied on technically challenging neonatal injections. Here, we performed extensive analysis of AML engraftment in adult NSG mice using tail vein injection. Of the 35 AML samples analyzed, 66% showed bone marrow engraftment over 0.1%. Further, 37% showed high levels of engraftment (>10%), with some as high as 95%. A 2–44-fold expansion of AML cells was often seen. Secondary and tertiary recipients showed consistent engraftment, with most showing further AML cell expansion. Engraftment did not correlate with French–American–British subtype or cytogenetic abnormalities. However, samples with FLT3 mutations showed a higher probability of engraftment than FLT3 wild type. Importantly, animals developed organomegaly and a wasting illness consistent with advanced leukemia. We conclude that the NSG xenotransplantation model is a robust model for human AML cell engraftment, which will allow better characterization of AML biology and testing of new therapies.

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References

  1. 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 

  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  Google Scholar 

  3. 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  Google Scholar 

  4. Christianson SW, Greiner DL, Hesselton RA, Leif JH, Wagar EJ, Schweitzer IB et al. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. J Immunol 1997; 158: 3578–3586.

    CAS  PubMed  Google Scholar 

  5. Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 1995; 154: 180–191.

    CAS  PubMed  Google Scholar 

  6. Feuring-Buske M, Gerhard B, Cashman J, Humphries RK, Eaves CJ, Hogge DE . Improved engraftment of human acute myeloid leukemia progenitor cells in beta 2-microglobulin-deficient NOD/SCID mice and in NOD/SCID mice transgenic for human growth factors. Leukemia 2003; 17: 760–763.

    Article  CAS  Google Scholar 

  7. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 2005; 174: 6477–6489.

    Article  CAS  Google Scholar 

  8. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315–1321.

    Article  CAS  Google Scholar 

  9. Murphy KM, Levis M, Hafez MJ, Geiger T, Cooper LC, Smith BD et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn 2003; 5: 96–102.

    Article  CAS  Google Scholar 

  10. Sheehan D, Hrapchak B . Theory and Practice of Histotechnology. Second edn. St Louis: Mosby, 1980.

    Google Scholar 

  11. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Int Med 1985; 103: 620–625.

    Article  CAS  Google Scholar 

  12. Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.

    Article  CAS  Google Scholar 

  13. Agliano A, Martin-Padura I, Mancuso P, Marighetti P, Rabascio C, Pruneri G et al. Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer 2008; 123: 2222–2227.

    Article  CAS  Google Scholar 

  14. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . Efficient tumour formation by single human melanoma cells. Nature 2008; 456: 593–598.

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Taussig DC, Miraki-Moud F, Anjos-Afonso F, Pearce DJ, Allen K, Ridler C et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 2008; 112: 568–575.

    Article  CAS  Google Scholar 

  17. Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP . Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 2007; 139: 351–362.

    Article  CAS  Google Scholar 

  18. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 2005; 106: 1565–1573.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Catherine Keefer and Anthony Secreto of the Stem Cell and Xenograft Core at the University of Pennsylvania for their excellent technical assistance with NSG mice, leukemia cell injections, and animal health monitoring; Beth A Burke and Craig Jordan for critical evaluation of manuscript, design, and placement of figures; and Minu Samanta for analysis of FLT3 mutation expression in select AML samples. We also thank Neena J Panackal and Daniel Martinez from the Pathology Core Laboratories at the Children's Hospital of Philadelphia for processing mouse tissues and performing H & E stains on liver and kidney of engrafted recipients. MC was supported in part by the Leukemia Lymphoma Society of America.

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Correspondence to M Carroll.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Sanchez, P., Perry, R., Sarry, J. et al. A robust xenotransplantation model for acute myeloid leukemia. Leukemia 23, 2109–2117 (2009). https://doi.org/10.1038/leu.2009.143

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