Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis leukemogenesis and therapeutic response

摘要

Cell line-derived xenografts (CDX) or patient-derived xenografts (PDX), in immune deficient mice, have revolutionized our understanding of normal and malignant human hematopoiesis. Transgenic approaches further improved in vivo hematological research, allowing the development of human cytokine producing mice, which show superior human cell engraftment. The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdc^scid Il2rγ^tm1Sug/Jic), and the NSG (NOD/SCID-IL2Rγ^−/−, NOD.Cg-Prkdc^scidIl2rγ^tm1Wjl/SzJ) mouse and their human cytokine-producing (IL-3, GM-CSF, and SCF) counterparts (huNOG and NSGS), rely partly on a mutation in the DNA repair protein PRKDC causing a severe combined immune deficiency phenotype rendering the mice less tolerant to DNA damaging therapeutics, thereby limiting their usefulness in the investigation of novel AML therapeutics. NRG (NOD/RAG1/2^−/−IL2Rγ^−/−) mice show equivalent immune ablation through a defective recombination activation gene (RAG) leaving DNA damage repair intact and human cytokine producing NRGS mice were generated, improving myeloid engraftment. Our findings indicate that unconditioned NRG and NRGS mice can harbor established AML CDX, and can tolerate aggressive induction chemotherapy at higher doses than NSG mice without overt toxicity. However, unconditioned NRGS mice developed less clinically relevant disease with CDXs forming solid tumors throughout the body, while unconditioned NRG mice were incapable of efficiently supporting PDX or human hematopoietic stem cell engraftment. These findings emphasize the contextually dependent utility of each of these powerful new strains in the study of normal and malignant human hematopoiesis. Thus, the choice of mouse strain cannot be random, but must be based on the experimental outcomes and questions to be addressed.