Mice deficient for Spa‐1 encoding Rap GTPase‐activating protein develop myeloproliferative disorder (MPD) of late onset with frequent blast crises. The mechanisms for MPD development as well as the reasons for long latency, however, remain elusive. We demonstrate here that preleukemic, disease‐free Spa‐1−/− mice show reduced steady‐state hematopoiesis and attenuated resistance to whole body γ‐ray irradiation, which are attributable to the sustained p53 response in hematopoietic progenitor cells (HPCs). Preleukemic Spa‐1−/− HPCs show c‐Myc overexpression with increased p19Arf as well as enhanced γH2AX expression with activation of Atm/Chk pathway. We also show that deregulated Rap signaling in the absence of Spa‐1 enhances post‐transcriptional c‐Myc stability and induces DNA damage in a p38MAPK‐dependent manner, leading to p53 activation. Genetic studies indicate that the introduction of p53+/− and p53−/− mutations in Spa‐1−/− mice results in the acceleration of typical MPD and rapid development of blastic leukemia, respectively. These results suggest that increased c‐Myc expression and DNA damage in HPCs precede MPD development in Spa‐1−/− mice, and the resulting p53 response functions as a barrier for the onset of MPD and blast crises progression. (Cancer Sci 2011; 102: 784–791)