Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice

Ekaterina Viktorovna Baidyuk, E.V. Belotserkovskaya, L.L. Girshova, V.A. Golotin, K.A. Levchuk, M.L. Vasyutina, Ya.A. Portnaya, E.V. Shchelina, O.G. Bredneva, A.V. Petukhov, A.Yu. Zaritskey, O.N. Demidov,

DOI:

https://doi.org/10.21320/2500-2139-2021-14-4-414-425

Background. Up to the present the survival rates of acute myeloid leukemia (AML) patients have remained low. A successful OML management presupposes generating personalized models of the disease. The most promising research activity in this field is creation of AML patient-derived xenograft models using the advanced strain of immunodeficient humanized NSG-SGM3 mice.

Aim. To generate AML patient-derived xenograft models using immunodeficient NSG-SGM3 mice.

Materials & Methods. The creation of PDX models was based on bone marrow aspirates taken from 4 patients with newly diagnosed AML who were treated at the VA Almazov National Medical Research Center. Patient-derived tumor cells were transplanted to NSG-SGM3 mice. Test experiment consisted in injecting AML cells OCI-АМL2 and HL60 in NSG-SGM3 mice. The efficacy of tumor engraftment was evaluated in terms of physical condition of animals and laboratory tests (blood count, blood smear, PCR, and flow cytofluorometry).

Results. The engraftment of applied tumor cells derived from 4 AML patients was achieved in half (2 out of 4) of the mice. In 2 mice with successful transplantation leukocytosis was reported. Blast cells were identified in peripheral blood on Day 30 after transplantation. The mice with injected AML cells OCI-АМL2 and HL60 showed a more aggressive course of disease. Among tested approaches to evaluate tumor engraftment in mouse recipients, the PCR method was marked by highest sensitivity.

Conclusion. The use of immunodeficient humanized NSG-SGM3 mice enables successful generation of AML patient-derived xenograft models.

  • Ekaterina Viktorovna Baidyuk Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064
  • E.V. Belotserkovskaya Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064
  • L.L. Girshova Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • V.A. Golotin Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064
  • K.A. Levchuk VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • M.L. Vasyutina VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • Ya.A. Portnaya Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064
  • E.V. Shchelina VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • O.G. Bredneva VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • A.V. Petukhov Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; НТУ «Сириус», Олимпийский пр-т, д. 1, Сочи, Российская Федерация, 354340
  • A.Yu. Zaritskey VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • O.N. Demidov Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340 ; ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064; НТУ «Сириус», Олимпийский пр-т, д. 1, Сочи, Российская Федерация, 354340
  1. Saultz JN, Garzon R. Acute Myeloid Leukemia: A Concise Review. J Clin Med. 2016;5(3):33. doi: 10.3390/jcm5030033. DOI: https://doi.org/10.3390/jcm5030033
  2. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487–94. doi: 10.1200/jco.2010.30.1820. DOI: https://doi.org/10.1200/JCO.2010.30.1820
  3. Patel SA, Gerber JM. A User’s Guide to Novel Therapies for Acute Myeloid Leukemia. Clin Lymphoma Myel Leuk. 2020;20(5):277–88. doi: 10.1016/j.clml.2020.01.011. DOI: https://doi.org/10.1016/j.clml.2020.01.011
  4. Levine RL. Molecular pathogenesis of AML: translating insights to the clinic. Best Pract Res Clin Haematol. 2013;26(3):245–8. doi: 10.1016/j.beha.2013.10.003. DOI: https://doi.org/10.1016/j.beha.2013.10.003
  5. Mitra A, Mishra L, Li S. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol. 2013;31(6):347–54. doi: 10.1016/j.tibtech.2013.03.006. DOI: https://doi.org/10.1016/j.tibtech.2013.03.006
  6. Bruserud О, Gjertsen BT, Foss B, et al. New strategies in the treatment of acute myelogenous leukemia (AML): In vitro culture of AML cells—The present use in experimental studies and the possible importance for future therapeutic approaches. Stem Cells. 2001;19(1):1–11. doi: 10.1634/stemcells.19-1-1. DOI: https://doi.org/10.1634/stemcells.19-1-1
  7. Ryningen A, Stapnes C, Bruserud О. Clonogenic acute myelogenous leukemia cells are heterogeneous with regard to regulation of differentiation and effect of epigenetic pharmacological targeting. Leuk Res. 2007;31(9):1303–13. doi: 10.1016/j.leukres.2007.01.019. DOI: https://doi.org/10.1016/j.leukres.2007.01.019
  8. Непомнящих Т.С., Гаврилова Е.В., Максютов Р.А. Некоторые аспекты использования алло- и ксенографтных моделей при разработке противораковых вакцин и онколитических вирусов. Медицинская иммунология. 2019;21(2):221–30. doi: 10.15789/1563-0625-2019-2-221-230.
  9. [Nepomnyashchikh TS, Gavrilova EV, Maksyutov RA. Selected aspects of allo- and xenograft model applications for developing novel anti-cancer vaccines and oncolytic viruses. Medical Immunology (Russia). 2019;21(2):221–30. doi: 10.15789/1563-0625-2019-2-221-230. (In Russ)] DOI: https://doi.org/10.15789/1563-0625-2019-2-221-230
  10. Shan WL, Ma XL. How to establish acute myeloid leukemia xenograft models using immunodeficient mice. Asian Pacif J Cancer Prev. 2013;14(12):7057–63. doi: 10.7314/apjcp.2013.14.12.7057. DOI: https://doi.org/10.7314/APJCP.2013.14.12.7057
  11. Mambet C, Chivu-Economescu M, Matei L, et al. Murine models based on acute myeloid leukemia-initiating stem cells xenografting. World J Stem Cells. 2018;10(6):57–65. doi: 10.4252/wjsc.v10.i6.57. DOI: https://doi.org/10.4252/wjsc.v10.i6.57
  12. Wunderlich M, Mizukawa B, Chou FS, et al. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model. Blood. 2013;121(12):e90–e97. doi: 10.1182/blood-2012-10-464677. DOI: https://doi.org/10.1182/blood-2012-10-464677
  13. Saland E, Boutzen H, Castellano R, et al. A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia. Blood Cancer J. 2015;5(3):e297. doi: 10.1038/bcj.2015.19. DOI: https://doi.org/10.1038/bcj.2015.19
  14. Her Z, Yong KSM, Paramasivam K, et al. An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia. J Hematol Oncol. 2017;10(1):162. doi: 10.1186/s13045-017-0532-x. DOI: https://doi.org/10.1186/s13045-017-0532-x
  15. Johanna I, Straetemans T, Heijhuurs S, et al. Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells. J Immunother Cancer. 2019;7(1):69. doi: 10.1186/s40425-019-0558-4. DOI: https://doi.org/10.1186/s40425-019-0558-4
  16. Ruzicka M, Koenig LM, Formisano S, et al. RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade. Leukemia. 2020;34(4):1017–26. doi: 10.1038/s41375-019-0639-x. DOI: https://doi.org/10.1038/s41375-019-0639-x
  17. Wunderlich M, Chou F-S, Link KA, et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010;24(10):1785–8. doi: 10.1038/leu.2010.158. DOI: https://doi.org/10.1038/leu.2010.158
  18. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12(11):786–98. doi: 10.1038/nri3311. DOI: https://doi.org/10.1038/nri3311
  19. Theocharides AP, Rongvaux A, Fritsch K, et al. Humanized hemato-lymphoid system mice. Haematologica. 2016;101(1):5–19. doi: 10.3324/haematol.2014.115212. DOI: https://doi.org/10.3324/haematol.2014.115212
  20. Nara N, Miyamoto T. Direct and serial transplantation of human acute myeloid leukaemia into nude mice. Br J Cancer. 1982;45(5):778–82. doi: 10.1038/bjc.1982.120. DOI: https://doi.org/10.1038/bjc.1982.120
  21. Okada S, Vaeteewoottacharn K, Kariya R. Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models. Cells. 2019;8(8):889. doi: 10.3390/cells8080889. DOI: https://doi.org/10.3390/cells8080889
  22. Sanchez PV, Perry RL, Sarry JE, et al. A robust xenotransplantation model for acute myeloid leukemia. Leukemia. 2009;23(11):2109–17. doi: 10.1038/leu.2009.143. DOI: https://doi.org/10.1038/leu.2009.143
  23. Krevvata M, Shan X, Zhou C, et al. Cytokines increase engraftment of human acute myeloid leukemia cells in immunocompromised mice but not engraftment of human myelodysplastic syndrome cells. 2018;103(6):959–71. doi: 10.3324/haematol.2017.183202. DOI: https://doi.org/10.3324/haematol.2017.183202
  24. Billerbeck E, Barry WT, Mu K, et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγ(null) humanized mice. Blood. 2011;117(11):3076–86. doi: 10.1182/blood-2010-08-301507. DOI: https://doi.org/10.1182/blood-2010-08-301507
  25. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196. DOI: https://doi.org/10.1182/blood-2016-08-733196
  26. Osman J, Murad AM, Chin SF, et al. Highly Sensitive and Reliable Human Sex Determination Using Multiplex PCR. Asia Pacif J Mol Med. 2014;4:1–4.
  27. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–30. doi: 10.1038/nri2017. DOI: https://doi.org/10.1038/nri2017
  28. Voin V, Khalid S, Shrager S, et al. Neuroleukemiosis: Two Case Reports. Cureus. 2017;9(7):e1529. doi: 10.7759/cureus.1529. DOI: https://doi.org/10.7759/cureus.1529
  29. Almosailleakh M, Schwaller J. Murine Models of Acute Myeloid Leukaemia. Int J Mol Sci. 2019;20(2):453. doi: 10.3390/ijms20020453. DOI: https://doi.org/10.3390/ijms20020453
  30. Agliano A, Martin-Padura I, Mancuso P, 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(9):2222–7. doi: 10.1002/ijc.23772. DOI: https://doi.org/10.1002/ijc.23772
  31. Terpstra W, Prins A, Visser T, et al. Conditions for engraftment of human acute myeloid leukemia (AML) in SCID mice. 1995;9(9):1573–7.
  32. Lumkul R, Gorin N, Malehorn M, et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. 2002;16(9):1818–26. doi: 10.1038/sj.leu.2402632. DOI: https://doi.org/10.1038/sj.leu.2402632
  33. Martin-Padura I, Agliano A, Marighetti P, et al. Sex-related efficiency in NSG mouse engraftment. Blood. 2010;116(14):2616–7. doi: 10.1182/blood-2010-07-295584. DOI: https://doi.org/10.1182/blood-2010-07-295584
  34. Woiterski J, Ebinger M, Witte KE, et al. Engraftment of low numbers of pediatric acute lymphoid and myeloid leukemias into NOD/SCID/IL2Rcγnull mice reflects individual leukemogenecity and highly correlates with clinical outcome. Int J Cancer. 2013;133(7):1547–56. doi: 10.1002/ijc.28170. DOI: https://doi.org/10.1002/ijc.28170
  35. 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(5):1761–72. doi: 10.1182/blood.V94.5.1761. DOI: https://doi.org/10.1182/blood.V94.5.1761.417k23_1761_1772
  36. Pearce DJ, Taussig D, Zibara K, et al. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. 2006;107(3):1166–73. doi: 10.1182/blood-2005-06-2325. DOI: https://doi.org/10.1182/blood-2005-06-2325
  37. Monaco G, Konopleva M, Munsell M, et al. Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival. Stem Cells. 2004;22(2):188–201. doi: 10.1634/stemcells.22-2-188. DOI: https://doi.org/10.1634/stemcells.22-2-188
  38. 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(5):889–97. doi: 10.1038/sj.leu.2401777. DOI: https://doi.org/10.1038/sj.leu.2401777
  39. Culen M, Kosarova Z, Jeziskova I, et al. The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice. J Cancer Res Clin Oncol. 2018;144(7):1239–51. doi: 10.1007/s00432-018-2652-2. DOI: https://doi.org/10.1007/s00432-018-2652-2

Keywords:

xenograft model, immunodeficient humanized mice, AML, NSG-SGM3 mice

License

Copyright (c) 2021 Clinical Oncohematology

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Downloads

Download data is not yet available.

Author Biography

  • Ekaterina Viktorovna Baidyuk, Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064, ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064

    PhD in Biology

Downloads

Published

01.10.2021

Issue

Vol. 14 No. 4 (2021)
EXPERIMENTAL STUDIES

How to Cite

Baidyuk E.V., Belotserkovskaya E.V., Girshova L.L., et al. Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice. Clinical Oncohematology. Basic Research and Clinical Practice. 2021;14(4):414–425. doi:10.21320/2500-2139-2021-14-4-414-425.

Most read articles by the same author(s)

1 2 3 > >>