MCM8- and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53-Dependent Myeloid Tumors.
Cell Rep
; 28(11): 2851-2865.e4, 2019 Sep 10.
Article
en En
| MEDLINE
| ID: mdl-31509747
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Daño del ADN
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Regulación Leucémica de la Expresión Génica
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Diferenciación Celular
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Proteína p53 Supresora de Tumor
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Neoplasias Hematológicas
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Proteínas de Mantenimiento de Minicromosoma
Límite:
Animals
Idioma:
En
Año:
2019
Tipo del documento:
Article