Genetically modified non-human animals and methods of use thereof

1. A method of transplanting human cancer cells, comprising:

transplanting human cancer cells into a genetically modified, immunodeficient mouse; and

transplanting human hematopoietic cells into the genetically modified, immunodeficient mouse,

wherein the genetically modified, immunodeficient mouse comprises in its genome a recombination activating gene 2 (Rag-2) gene knock-out, an IL2 receptor gamma chain (IL2 rg) gene knock-out, a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus, an insertion of a nucleic acid encoding a human SIRPA polypeptide, and a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide is operably linked to a promoter, and wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide.

2. The method of claim 1 , wherein the human cancer cells are primary human cancer cells isolated from a patient.

3. The method of claim 2 , wherein the human cancer cells and the human hematopoietic cells are isolated from the same patient.

4. The method of claim 1 , wherein the human cancer cells are from a cancer cell line.

5. The method of claim 1 , wherein the human cancer cells are selected from leukemia cells, breast cancer cells, lung cancer cells, and melanoma cells.

6. The method of claim 5 , wherein the human cancer cells are leukemia cells.

7. The method of claim 5 , wherein the human cancer cells are melanoma cells.

8. The method of claim 1 , wherein the human hematopoietic cells comprise CD34+cells.

9. The method of claim 1 , wherein the human SIRPA polypeptide is a biologically active fragment of a full-length human SIRPA polypeptide.

10. A method of human hematopoietic cell engraftment, comprising:

administering at least one human hematopoietic cell to a genetically modified, immunodeficient mouse, wherein the genetically modified, immunodeficient mouse comprises in its genome a recombination activating gene 2 (Rag-2) gene knock-out, an IL2 receptor gamma chain (IL2 rg) gene knock-out, a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus, an insertion of a nucleic acid encoding a human SIRPA polypeptide, and a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide is operably linked to a promoter, and wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide, and wherein the method does not comprise sub-lethally irradiating the genetically modified, immunodeficient mouse or treating the genetically modified, immunodeficient mouse with a radiomimetic drug prior to the administering.

11. The method of claim 10 , wherein the human SIRPA polypeptide is a biologically active fragment of a full-length human SIRPA polypeptide.

12. The method of claim 10 , wherein the human hematopoietic cells comprise CD34+cells.