MCM8- and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53-Dependent Myeloid Tumors

Hematopoiesis is particularly sensitive to DNA damage. Myeloid tumor incidence increases in patients with DNA repair defects and after chemotherapy. It is not known why hematopoietic cells are highly vulnerable to DNA damage. Addressing this question is complicated by the paucity of mouse models of hematopoietic malignancies due to defective DNA repair. We show that DNA repair-deficient Mcm8- and Mcm9-knockout mice develop myeloid tumors, phenocopying prevalent myelodysplastic syndromes. We demonstrate that these tumors are preceded by a lifelong DNA damage burden in bone marrow and that they acquire proliferative capacity by suppressing signaling of the tumor suppressor and cell cycle controller RB, as often seen in patients. Finally, we found that absence of MCM9 and the tumor suppressor Tp53 switches tumorigenesis to lymphoid tumors without precedent myeloid malignancy. Our results demonstrate that MCM8/9 deficiency drives myeloid tumor development and establishes a DNA damage burdened mouse model for hematopoietic malignancies. [Display omitted] •MCM8−/− and MCM9−/− mice show lifelong increased DNA damage in their bone marrow•The mice develop myeloid tumors resembling human myelodysplastic syndrome as they age•Loss of RB-mediated cell cycle control allows myeloid tumor proliferation•Additional loss of TP53 switches tumor development to aggressive T cell lymphoma Lutzmann et al. show that MCM8- or MCM9-deficient mice suffer chronic DNA damage, causing myeloid tumors, resembling human myelodysplastic syndromes, during aging. These tumors lose RB-mediated cell cycle control, cause splenomegaly, and preclude progressively normal hematopoiesis. Additional loss of the tumor suppressor Tp53 switches tumor development to T cell lymphoma.