Genetically modified non-human animals expressing human EPO

A genetically modified mouse immunodeficient for an endogenous immune system, wherein the genetically modified mouse is an EPOh/m IL-3h/h GM-CSFh/h TPOh/h SIRPαh/h Rag2null IL2rgnull mouse comprising:

• an erythropoietin (EPO) knock-in allele comprising a nucleic acid sequence that encodes a human erythropoietin (hEPO) protein operably linked to an endogenous mouse (EPO) gene promoter at the mouse EPO gene locus in the genome of the genetically modified mouse, wherein the EPO knock-in allele comprises a replacement of at least some of an endogenous mouse EPO coding sequence, wherein the mouse is heterozygous for the EPO knock-in allele (EPOh/m), wherein the mouse expresses the hEPO protein, and wherein the hEPO protein possesses wild-type human EPO signaling function;
• an interleukin 3 (IL-3) knock-in allele comprising a nucleic acid sequence that encodes a human interleukin 3 (hIL3) protein operably linked to an endogenous mouse IL-3 gene promoter at the mouse IL-3 gene locus in the genome of the genetically modified mouse, wherein the IL-3 knock-in allele comprises a replacement of at least some of an endogenous mouse IL-3 coding sequence, wherein the mouse is homozygous for the IL-3 knock-in allele (IL-3h/h), wherein the mouse expresses the hIL-3 protein, and wherein the hIL-3 protein possesses wild-type human IL-3 signaling function;
• a granulocyte-macrophage colony stimulating factor 2 (GM-CSF) knock-in allele comprising a nucleic acid sequence that encodes a human granulocyte-macrophage colony stimulating factor 2 (hGM-CSF) protein operably linked to an endogenous mouse GM-CSF gene promoter at the mouse GM-CSF gene locus in the genome of the genetically modified mouse, wherein the GM-CSF knock-in allele comprises a replacement of at least some of an endogenous mouse GM-CSF coding sequence, wherein the mouse is homozygous for the GM-CSF knock-in allele (GM-CSFh/h) wherein the mouse expresses the hGM-CSF protein, and wherein the hGM-CSF protein possesses wild-type human GM-CSF signaling function;
• a thrombopoietin (TPO) knock-in allele comprising a nucleic acid sequence that encodes a human thrombopoietin (hTPO) protein operably linked to an endogenous mouse TPO gene promoter at the mouse TPO gene locus in the genome of the genetically modified mouse, wherein the TPO knock-in allele comprises a replacement of at least some of an endogenous mouse TPO coding sequence, wherein the mouse is homozygous for the TPO knock-in allele (TPOh/h), wherein the mouse expresses the hTPO protein, and wherein the hTPO protein possesses wild-type human TPO signaling function;
• and
• a signal-regulatory protein alpha (SIRPα) knock-in allele comprising a nucleic acid sequence that encodes a humanized signal-regulatory protein alpha (hSirpa) protein operably linked to an endogenous mouse SIRPα gene promoter at the mouse SIRPα gene locus in the genome of the genetically modified mouse, wherein the SIRPα knock-in allele comprises a replacement of a portion of an endogenous mouse SIRPα coding sequence, wherein the mouse is homozygous for the SIRPα knock-in allele (SIRPαh/h), wherein the mouse expresses the hSIRPα protein, wherein the hSIRPα protein comprises an extracellular domain of a wild-type human SIRPα protein and a signaling domain of an endogenous mouse SIRPα protein, and wherein the hSIRPα protein possesses wild-type human SIRPα receptor function.