TY - JOUR
T1 - Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner
AU - Haupt, Sue
AU - Mitchell, Catherine
AU - Corneille, Vincent
AU - Shortt, Jake
AU - Fox, Stephen
AU - Pandolfi, Pier Paolo
AU - Castillo-Martin, Mireia
AU - Bonal, Dennis M.
AU - Cordon-Cardo, Carlos
AU - Lozano, Guillermina
AU - Haupt, Ygal
PY - 2013/6/1
Y1 - 2013/6/1
N2 - p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers. In healthy cells these two key tumor suppressors exist in a positive regulatory loop, promoting cell death and cellular senescence. However, the influence of their interplay on tumorigenesis has not been explored directly in vivo. The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53wildtype/R172H) that recapitulates a frequent p53 mutation (p53R175H) in human sporadic and Li-Fraumeni cancers. These mice with PML displayed perturbation of the hematopoietic compartment, manifested either as lymphoma or extramedullary hematopoiesis (EMH). EMH was associated with peripheral blood leucocytosis and macrocytic anemia, suggestive of myeloproliferative- myelodysplastic overlap. In contrast, a complete loss of PML from these mice resulted in a marked alteration in tumor profile. While the incidence of lymphomas was unaltered, EMH was not detected and the majority of mice succumbed to sarcomas. Further, males lacking PML exhibited a high incidence of soft tissue sarcomas and reduced survival, while females largely developed osteosarcomas, without impact on survival. Together, these findings demonstrate that PML is an important tumor suppressor dictating disease development in a pertinent mouse model of human cancer. Key Points: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative/ myelodysplastic overlap. (2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC).
AB - p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers. In healthy cells these two key tumor suppressors exist in a positive regulatory loop, promoting cell death and cellular senescence. However, the influence of their interplay on tumorigenesis has not been explored directly in vivo. The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53wildtype/R172H) that recapitulates a frequent p53 mutation (p53R175H) in human sporadic and Li-Fraumeni cancers. These mice with PML displayed perturbation of the hematopoietic compartment, manifested either as lymphoma or extramedullary hematopoiesis (EMH). EMH was associated with peripheral blood leucocytosis and macrocytic anemia, suggestive of myeloproliferative- myelodysplastic overlap. In contrast, a complete loss of PML from these mice resulted in a marked alteration in tumor profile. While the incidence of lymphomas was unaltered, EMH was not detected and the majority of mice succumbed to sarcomas. Further, males lacking PML exhibited a high incidence of soft tissue sarcomas and reduced survival, while females largely developed osteosarcomas, without impact on survival. Together, these findings demonstrate that PML is an important tumor suppressor dictating disease development in a pertinent mouse model of human cancer. Key Points: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative/ myelodysplastic overlap. (2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC).
KW - EMH
KW - Lymphoma
KW - Mutant p53
KW - Myelodysplastic overlap
KW - Myeloproliferative overlap
KW - P19ARF
KW - PML
KW - Sarcoma
UR - http://www.scopus.com/inward/record.url?scp=84878568273&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878568273&partnerID=8YFLogxK
U2 - 10.4161/cc.24805
DO - 10.4161/cc.24805
M3 - Article
C2 - 23656786
AN - SCOPUS:84878568273
SN - 1538-4101
VL - 12
SP - 1722
EP - 1731
JO - Cell Cycle
JF - Cell Cycle
IS - 11
ER -