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AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3

Leukemia volume 24, pages 1785–1788 (2010)Cite this article

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Despite major advances in human to mouse xenografts, most of the human acute myeloid leukemia (AML) samples fail to adequately engraft available strains of mice. The reasons for the disparate results with AML samples remain unclear, but likely include elements of homing, survival in a foreign niche, expansion in the absence of specific human growth factors and supporting stromal cells, escape from immune surveillance and residual innate immunity in the mice, as well as intrinsic differences among AML samples. One general strategy for improving engraftment has been the development and use of increasingly immunodeficient mouse strains (reviewed in1). For example, targeting of the IL2RG gene in the NOD/SCID (NS) strain by either complete knockout or truncation of the intracellular portion (NOD/LtSz-scid IL2RG: NSG and NOD/shi-scid IL2RG, respectively) was shown to diminish innate immunity, in particular macrophage function and NK activity, thereby improving engraftment by normal human CD34+ cells and AML cells.2, 3 Alternatively, transgenic expression of hSCF, hGM-CSF and hIL-3 (three non- or poorly cross-reacting cytokines) in the NOD/SCID background (NOD/LtSz-scid -SGM3, NSS) led to improvements in expansion of normal human myeloid cells, as well as slight gains in engraftment of AML samples.4, 5

Multiple mechanisms could be involved in these differences. To initiate a successful graft, cells must first properly home to the BM. To determine the variation of homing in the four mouse strains under investigation, we injected 10 million leukemia cells and analyzed the BM 24 h after injection. The level of engraftment was significantly higher in IL2RG-deficient mice (NSG and NSGS) compared with the other two strains (Figure 2b). Although absolute homing efficiency was low (ranging from approximately 0.04% in NS and NSS mice to 0.1% in NSG and NSGS), these levels were sufficient to initiate lethal disease in NSGS and NSS mice within 4–5 weeks (Figure 2a). These data highlight the critical role of innate immunity for the initial stage of engraftment, whereas expression of human myeloid cytokines alone does not significantly alter it. In addition, we examined engraftment by measuring human AML cells in the BM and PB 1 month after injection. BM aspiration showed the highest chimerism in NSGS mice (Figure 2c, top). NSG and NSS mice also clearly outperformed the NS mice in this test, with the NS mice seeming to be essentially negative for engraftment. PB measurement of the grafts showed essentially the same results (Figure 2c, bottom). Moreover, engraftment is significantly increased in human cytokine-expressing mice (NSGS and NSS) compared with their counterparts (NSG and NS, respectively). Thus, the reduced innate immune response increases initial homing efficiency to the marrow and may support subsequent growth/survival of the cells. In contrast, human cytokines do not affect homing efficiency but provide cell proliferation and survival signals that become more measurable over time. These effects seem additive, as evidenced by the superior engraftment observed in NSGS mice relative to NSG or NSS mice.

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Acknowledgements

We thank Leonard Shultz for help with the IL2RG PCR conditions, the Comprehensive Mouse and Cancer Core of Cincinnati Children's Hospital for help with mouse experiments, Susumu Goyama for valuable discussion and suggestions, and Christina Sexton and Mahesh Shrestha for technical assistance. This study was supported by NIH grants CA118319 and CA140518, Gabrielle's Angel Foundation for Cancer Research and DOD Grant PR081404 (JCM). MC was supported in part by the Art Rhodes Fund for Leukemia Research at the Abramson Cancer Institute of the University of Pennsylvania.

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  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    M Wunderlich, F-S Chou, K A Link & J C Mulloy

  2. Division of Hematology and Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    B Mizukawa

  3. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    R L Perry

  4. Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA

    M Carroll

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Correspondence to J C Mulloy.

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Wunderlich, M., Chou, FS., Link, K. et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia 24, 1785–1788 (2010). https://doi.org/10.1038/leu.2010.158

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