title: Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner.
abstract: 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 (p53 (wild-type/R172H) ) that recapitulates a frequent p53 mutation (p53 (R175H) ) 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.
  
  
  CONCLUSIONS
  (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).
authors: Research Division, Peter MacCallum Cancer Centre, East Melbourne, VIC Australia. sue.haupt@petermac.org
authors: Sue
authors: S
authors: Haupt
authors: Catherine
authors: C
authors: Mitchell
authors: Vincent
authors: V
authors: Corneille
authors: Jake
authors: J
authors: Shortt
authors: Stephen
authors: S
authors: Fox
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Mireia
authors: M
authors: Castillo-Martin
authors: Dennis M
authors: DM
authors: Bonal
authors: Carlos
authors: C
authors: Cordon-Cardo
authors: Guillermina
authors: G
authors: Lozano
authors: Ygal
authors: Y
authors: Haupt
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000209:etiology; D000071156:Promyelocytic Leukemia Protein; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: EMH; PML; lymphoma; mutant p53; myelodysplastic overlap; myeloproliferative overlap; p19ARF; sarcoma
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