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Comparison of childhood leukemia initiating cell populations in NOD/SCID and NSG mice

Leukemia volume 26, pages 376–380 (2012)Cite this article

Leukemia initiating cells (LICs) are defined by their ability to generate leukemias in animal models and to self-renew by repopulating serial recipients. Recent findings suggest that multiple sub-populations of acute leukemia cells are capable of engrafting immune deficient mice raise important questions about the biology of these diseases.1, 2, 3 If several cell populations have LIC properties, what are the relationships of these stem cell populations to each other and which populations are most important to target with therapy? To address these questions, it is crucial to utilize assays that are capable of identifying any leukemia cells that possess stem cell properties. The recently developed NOD/LtSz-scid IL-2Rγc null (NSG) mouse is now considered a more permissive host for the growth and development of normal and acute myeloid leukemia cells than the nonobese diabetic severe combined immune deficient (NOD/SCID) strain.4, 5 In acute lymphoblastic leukemia (ALL) engraftment of high-risk cases has been reported to be slower in NOD/SCID than NSG but otherwise leukemias developed in both strains.6 However, another study reported that engraftment of T-ALL cells was improved using NSG mice.7 Observations that different populations of cells can engraft different mouse strains raise questions as to how the reports that used only NOD/SCID mice should be interpreted. NSG and NOD/SCID strains have not previously been directly and quantitatively compared for engraftment potential of pediatric LIC sub-populations using the same source of cells. Such studies should provide clear information as to the permissiveness of each strain and which sub-populations have LIC potential.

To address the question of whether multiple sub-populations of ALL cells have LIC content we compared sorted T- and B-ALL populations for their potential to engraft both strains (see Supplementary material for details). In the T-ALL cases, multiple populations were capable of engrafting NSG mice (Table 1). In 2 of 4 cases, reasonable levels of engraftment were observed with the CD34+/CD7+ (32–98%) and CD34− (90–98%) sub-populations. In contrast, only very low levels of engraftment were observed when these sub-populations were inoculated into NOD/SCIDs. The CD34+/CD7− subfraction represented only 0.81±0.5% of the total blast population in these cases at sorting. However, engraftment with this subfraction was observed in both NSG and NOD/SCID mice in every case, although higher levels were detected in NSG mice (21–99%) than in NOD/SCID (4–86%). Engraftment of CD34+/CD7− cells was more rapid than that of unsorted cells or any other population regardless of the mouse strain. Moreover, 30 to 100-fold fewer CD34+/CD7− cells were required to achieve engraftment levels equivalent to that observed with CD34− cells in NSG. Fluorescence in situ hybridization analyses confirmed engraftment of leukemia cells in the animals. The inoculated CD34+/CD7− cells underwent differentiation in vivo to produce leukemias with similar immunophenotypes to the patient samples at biopsy (Table 2). A minor fraction of these grafts were CD34+/CD7− (0.8±0.3%) consistent with self-renewal of this subfraction. When we investigated the self-renewal ability of these T-ALL sub-populations in both strains, engraftment of cells from recipients of CD34+/CD7+ and CD34− sub-populations was limited to 2–3 rounds (Table 2, Supplementary Figure 2). In contrast, engraftment levels remained relatively stable after 3–5 rounds of transplantation of cells from recipients of CD34+/CD7− cells. Engraftment was more rapid in these serial xenografts and consequently animals had to be killed at earlier time points than the primary recipients. Our finding suggests that multiple T-ALL populations can engraft NSG mice concurs with a report of engraftment of CD7+/CD1a− and CD7+/CD1a+ adult T-ALL cells in NSG mice, whereas engraftment was achieved in NOD/SCID mice with the CD7+/CD1a− sub-population only.7 Interestingly, when leukemia cells from primary NOD/SCID mice, that had been engrafted with CD7+/CD1a− cells were re-sorted both CD7+/CD1a− and CD7+/CD1a+ cells could engraft NSG mice.7 This observation suggests that the NOD/SCID environment may have had a role in the selection and adaptation of LICs, resulting in two populations with engrafting potential in NSG. This finding provides evidence for the concept of primary xenograft selection of cells with engrafting capacity.

Table 2 Immunophenotypic and karyotypic analyses of serial NSG xenografts
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Acknowledgements

We thank Mr Paul Virgo and staff of the Bristol Genetics Laboratory, the North Bristol NHS Trust, Dr Andrew Herman for cell sorting and the University of Bristol Faculty of Medical and the Veterinary Sciences Flow Cytometry Facility, Dr Michelle Cummins, Dr John Moppett and Oncology staff at the Bristol Royal Hospital for Children. We are grateful to the patients and their families who gave permission for their cells to be used for research. This work was supported by grants from the Department of Health and the National Blood Authority. This article presents independent research commissioned by the National Institute for Health Research (NIHR) under its Programme Grants scheme (RP-PG-0310-1003). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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  1. Bristol Institute for Transfusion Sciences, University of Bristol, Bristol, UK

    P Diamanti, C V Cox & A Blair

  2. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK

    P Diamanti, C V Cox & A Blair

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  1. P Diamanti
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Correspondence to A Blair.

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Diamanti, P., Cox, C. & Blair, A. Comparison of childhood leukemia initiating cell populations in NOD/SCID and NSG mice. Leukemia 26, 376–380 (2012). https://doi.org/10.1038/leu.2011.212

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