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An MDS xenograft model utilizing a patient-derived cell line

Leukemia volume 28, pages 1142–1145 (2014)Cite this article

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Animal models that faithfully recapitulate clinical features of myelodysplastic syndrome (MDS) have been difficult to establish. MDS are hematologic disorders associated with ineffective hematopoiesis, blood cytopenias, myeloid dysplasia and an increased risk of acute myeloid leukemia (AML). Although transplantation of primary AML cells into immunocompromised mice has been met with much success, primary MDS patient samples exhibit poor engraftment with no evidence of disease in recipient animals.1, 2, 3 The engraftment of primary MDS samples is complicated further by frequent outgrowth of normal HSC clones.4 These challenges underscore the current limitations and inefficiencies of engrafting primary MDS cells. Recent improvements in engrafting primary MDS cells have been observed when transplanting immunophenotypically defined HSC from the marrow of MDS patients or when co-injecting stromal cells engineered to produce non-cross-reacting human cytokines.5, 6 Unfortunately, even with the improved engraftment of primary MDS cells, mice do not succumb to features resembling human MDS, precluding the use of these models for pre-clinical testing. To circumvent the current limitations, we developed a model using immunocompromised recipient mice and a human MDS cell line (MDSL) derived from the non-leukemic phase of an MDS patient with refractory anemia-ringed sideroblasts.7, 8, 9 The MDSL line was derived as a subline of MDS92, and maintains factor dependency for cell growth, but has reduced differentiational capacity compared with MDS92.10 Herein, we report the successful engraftment of MDSL cells into NOD/SCID-IL2Rγ mice (NSG) and NSG-hSCF/hGM-CSF/hIL3 (NSGS) mice, and reproducible development of disease, including cytopenias, clonal expansion and host hematopoietic suppression. In addition, we show that the MDSL xenograft model is a useful tool for evaluating novel and existing therapeutics for MDS.

Intrafemoral BM aspirates of NSG at 53 days post transplant revealed an average human MDSL (CD45+CD33+) graft of 2% total marrow (Figure 1d). However, at time of death (82 days post transplant), MDSL cells progressively expanded to occupy ∼60% of the total marrow (Figure 1d). BM cellularity was determined for MDSL- and CD34+ cord blood-engrafted NSG mice 10 weeks post transplant. Although MDSL cells gradually expanded over time, the total cellularity of MDSL-engrafted marrows was 70% less than CD34+ cord blood-engrafted marrows (5 × 106 versus 22 × 106 cells/femur) (Figure 1e). Immunohistochemical examination of the BM from MDSL-engrafted NSG mice confirmed a hypocellular marrow, whereas control CD34+ cell-engrafted mice exhibited normal BM cellularity (Figure 1f). In MDSL-engrafted mice, we also observed bone remodeling at the endosteum (Figure 1f). These findings indicate that MDSL cells undergo clonal expansion whereas simultaneously displacing host-mouse BM cells.

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Acknowledgements

This work was supported by the Cincinnati Children’s Hospital Research Foundation, the American Society of Hematology (ASH), the National Institute of Health (RO1HL111103), and the Department of Defense grants to DTS and a NIH/NCRR Institutional Clinical and Translational Science Award (1UL1RR026314-01) to JCM; DTS is an ASH scholar and JCM is a leukemia and lymphoma scholar. The umbilical cord CD34+ samples were received through the Normal Donor Repository in the Translational Core Laboratory at Cincinnati Children's Research Foundation, which is supported through the NIDDK Center’s of Excellence in Experimental Hematology (P30DK090971). We thank the Mt Auburn Ob-Gyn associates and delivery nursing staff at the Christ Hospital (Cincinnati, OH, USA) for collecting cord blood (CD34+) samples from normal deliveries. We thank Jeff Bailey and Victoria Summey for assistance with transplantations and xenotransplantations (Comprehensive Mouse and Cancer Core). MDSL cells were kindly provided by Dr Kaoru Tohyama and are made available upon request (ktohyama@med.kawasaki-m.ac.jp or Daniel.Starczynowski@cchmc.org).

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Authors and Affiliations

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

    G W Rhyasen, M Wunderlich, J C Mulloy & D T Starczynowski

  2. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA

    G W Rhyasen & D T Starczynowski

  3. Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

    K Tohyama

  4. Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA

    G Garcia-Manero

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  1. G W Rhyasen
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  2. M Wunderlich
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  3. K Tohyama
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  6. D T Starczynowski
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Correspondence to D T Starczynowski.

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Rhyasen, G., Wunderlich, M., Tohyama, K. et al. An MDS xenograft model utilizing a patient-derived cell line. Leukemia 28, 1142–1145 (2014). https://doi.org/10.1038/leu.2013.372

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