Acute myeloid leukemia (AML) is the major form of adult acute leukemia. It is characterized by colonial expansion of malignant myeloid progenitors in bone marrow, resulting in insufficient generation of normal blood components to cause sever infection, fatigue, and hemorrhage in patients. p53 is a tumor suppressor that commonly mutates in human cancers. p53 mutations have profound effects on AML biology and are associated with the clinical aggressiveness and drug resistance. However, how p53 loss influences AML development remains to be determined. Mouse models recapitulating molecular alterations of human cancer are useful tools to dissect the in vivo roles of tumor suppressor genes and understand pathophysiology process of tumorogenesis. In my Ph.D. dissertation study, I established a mouse model of AML with p53 deficiency and oncogenic Kras activation (Kras-shp53). By exploiting well-established assays to assess self-renewal capabilities of normal and leukemic cells, I found that p53 deficiency provides one mechanism whereby committed myeloid progenitor cells acquire the capacity for indefinite self-renewal, which contributes to leukemogenesis. I also established that Kras-shp53 leukemic cells exhibit constitutive activation of Ras signaling and found that suppression of Spry4 gene (one of the negative regulators of Ras signaling) cooperates with Kras activation to induce leukemia/lymphoma. Finally, I established that p53 status determines the level of Ras signaling flux and predisposes the leukemias to differential responsiveness to MEK inhibition. All in all, my work has provided new insights into p53 tumor suppressive actions and AML biology, and has lead to design of better therapeutic strategies.