Transgenic expression of human cytokines in immunodeficient mice does not facilitate myeloid expansion of BCR-ABL1 transduced human cord blood cells

Abstract

Several attempts have been made to model chronic myeloid leukemia (CML) in a xenograft setting but expansion of human myeloid cells in immunodeficient mice has proven difficult to achieve. Lack of cross-reacting cytokines in the microenvironment of the mice has been proposed as a potential reason. In this study we have used NOD/SCID IL2–receptor gamma deficient mice expressing human SCF, IL-3 and GM-CSF (NSGS mice), that should be superior in supporting human, and particularly, myeloid cell engraftment, to expand BCR-ABL1 expressing human cells in order to model CML. NSGS mice transplanted with BCR-ABL1 expressing cells became anemic and had to be sacrificed due to illness, however, this was not accompanied by an expansion of human myeloid cells but rather we observed a massive expansion of human T-cells and macrophages/histiocytes. Importantly, control human cells without BCR-ABL1 expression elicited a similar reaction, although with a slight delay of disease induction, suggesting that while BCR-ABL1 contributes to the inflammatory reaction, the presence of normal human hematopoietic cells is detrimental for NSGS mice.

Development of Mast Cell and Eosinophil Hyperplasia and HLH/MAS-Like Disease in NSG-SGM3 Mice Receiving Human CD34+ Hematopoietic Stem Cells or Patient-Derived Leukemia Xenografts

“…Previous studies using the NSG-SGM3 mouse have reported the presence of increased mast cells in various tissues such as the lung, spleen, stomach, small intestine, heart, and skin. 6,17 We similarly observed low numbers of human mast cells in all of these tissues except the skin. In the skin we observed moderate numbers of mast cells positive for MCT, but these were negative for hNuMA1, indicating that they were murine mast cells.…”

“…This is the first report of the presence of high numbers of human mast cells in the pancreas. It is possible that they were present in the mice examined in previous studies 6,17 but this specific tissue was not examined. It is unclear why the pancreas is a target organ for mast cells in these mice, as no clear role has yet been described for mast cells in either pancreatic homeostasis or pancreatic disease.…”

“…62,81 Multilineage hematopoiesis occurs within 12 weeks. Another common use of NSG-SGM3 mice exploits their enhanced ability to engraft different types of human myeloid leukemia, 6,8,97,104 including human leukemia cell lines and leukemia patient-derived xenografts (PDXs). A less common leukemia model involves the implantation of human CD34þ HSCs that have been genetically modified via viral transduction to express leukemia-initiating factors.…”

“…A less common leukemia model involves the implantation of human CD34þ HSCs that have been genetically modified via viral transduction to express leukemia-initiating factors. 6,57,95 This study describes the development of 3 general categories of histopathologic features in naı ¨ve and humanized NSG-SGM3 mice and in NSG-SGM3 mice implanted with transduced hCD34þ HSCs or leukemia PDXs. These features are believed to be due to the expression of the 3 human transgenes for SCF, GM-CSF, and Il-3 on the NSG background.…”

Cancer Immunotherapies and Humanized Mouse Drug Testing Platforms

“…Furthermore, the residual mouse immune components, which mainly consist of macrophages and granulocytes may also interfere the responses. Efforts have been made to improve the human immune elements in the humanized mice, such as transgenically expression of different human growth factors and cytokines [112], [114], hydrodynamic tail vein injection of plasmid DNA encoding human cytokines [113], lentivirus or adeno-associated virus delivery of cytokines [115], [116], [117] and replacing the host genes with human counterparts [118], [119], [120]. Using genetically engineering technology, NSG-SGM3 mice (genetically engineered to produce IL-3, granulocyte/macrophage colony-stimulating factor (GM-CSF) and Steel factor (SF)), NSGW41 mice (KitW-41J allele), MISTRG (co-expressed M-CSF, IL-3, GM-CSF and thrombopoietin) and NSG-IL-15 (high expression of human IL-15) were established for improving the development and differentiation of HSCs, NKs and monocytes/macrophages [121], [122].…”