Calpastatin overexpression is associated to an increased frequency of spleen tumors. Most of CalpTG (TG) mice died with an abdominal distension due to a massive splenomegaly, there was no difference of survival rate between WT and CalpTG mice (A, n = 25/group). Among the 10 CalpTG mice sacrificed at 2 years, 7 had an apparently normal spleen but 3 were affected by splenic tumors, compressing abdominal organs (B). Aged WT mice spleens had a classical follicular architecture and white pulp containing regular lymphocytes (C, magnification ×50). Splenic architecture was disrupted in CalpTG tumoral spleens, white pulp could not be differentiated from red pulp (D, magnification ×50) and fibrosis was evident in the most severe cases (E, magnification ×50). Erythroblastic hyperplasia with evidence of dyserythropoiesis (*), and compact megacaryocytes clusters with nuclear atypia (arrows) were typical features of abnormal myeloid intrasplenic proliferation (F, magnification ×200). The partial loss of factor VIII expression by megacaryocytes (arrow) among clusters confirmed the myelodysplasic syndrome (G, magnification ×400).