A method for testing the effect of an agent that modulates cancer cell growth or survival, or for the in vivo evaluation of a cancer treatment involving the agent, the method comprising: administering the agent to a genetically modified mouse, wherein the genetically modified mouse comprises in its genome: a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide operably linked to the mouse M-CSF promoter and regulatory elements at the mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide operably linked to the mouse IL-3 promoter and regulatory elements at the mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide operably linked to the mouse GM-CSF promoter and regulatory elements at the mouse GM-CSF gene locus, a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide operably linked to the mouse TPO promoter and regulatory elements at the mouse TPO gene locus, and an insertion of a nucleic acid encoding a human S IRPA polypeptide operably linked to a human S IRPA promoter and regulatory elements, wherein the genetically modified mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human S IRPA polypeptide, and the human TPO polypeptide, and wherein the genetically modified mouse is immunodeficient, engrafted with human hematopoietic cells, and engrafted with human cancer cells; and assessing effect of the agent on cancer cell growth or survival in the genetically modified mouse. administering the agent to a genetically modified mouse, wherein the genetically modified mouse comprises in its genome: a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide operably linked to the mouse M-CSF promoter and regulatory elements at the mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide operably linked to the mouse IL-3 promoter and regulatory elements at the mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide operably linked to the mouse GM-CSF promoter and regulatory elements at the mouse GM-CSF gene locus, a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide operably linked to the mouse TPO promoter and regulatory elements at the mouse TPO gene locus, and an insertion of a nucleic acid encoding a human S IRPA polypeptide operably linked to a human S IRPA promoter and regulatory elements, wherein the genetically modified mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human S IRPA polypeptide, and the human TPO polypeptide, and wherein the genetically modified mouse is immunodeficient, engrafted with human hematopoietic cells, and engrafted with human cancer cells; and a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide operably linked to the mouse M-CSF promoter and regulatory elements at the mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide operably linked to the mouse IL-3 promoter and regulatory elements at the mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide operably linked to the mouse GM-CSF promoter and regulatory elements at the mouse GM-CSF gene locus, a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide operably linked to the mouse TPO promoter and regulatory elements at the mouse TPO gene locus, and an insertion of a nucleic acid encoding a human S IRPA polypeptide operably linked to a human S IRPA promoter and regulatory elements, wherein the genetically modified mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human S IRPA polypeptide, and the human TPO polypeptide, and wherein the genetically modified mouse is immunodeficient, engrafted with human hematopoietic cells, and engrafted with human cancer cells; and assessing effect of the agent on cancer cell growth or survival in the genetically modified mouse.