title: p53 loss of function enhances genomic instability and accelerates clonal evolution of murine myeloid progenitors expressing the p(210)BCR-ABL tyrosine kinase.
abstract: OBJECTIVE
  The p210 bcr-abl fusion protein has a key role in the pathogenesis of chronic myeloid leukemia (CML). However, its influence on disease progression to blast crisis is marginal and mostly due to its effect of impairing the genomic stability of clonal myeloid progenitors through pathways still largely unknown.
  
  
  METHODS
  To elucidate the role of p53 in CML progression we generated, from the 32D murine myeloid cell line, several clones co-expressing the E6 product gene of human papilloma virus (HPV) 16, which abrogates p53 function, and a temperature-sensitive bcr-abl construct encoding a fully active p210 protein only at the permissive temperature of 33 degrees C.
  
  
  RESULTS
  Co-expression of the two proteins resulted in a significant enlargement of the G(2)/M phase of cell cycle and in the appearance of a poly-aneuploid cell population. Furthermore, with continuous in vitro passages the p210 tyrosine kinase became dispensable for growth. Increased levels of cyclin B(1) and enhanced activity of its associated cyclin-dependent kinase (cdc2) became apparent during the clonal evolution of p210 bcr-abl-transduced 32D cell clones lacking p53.
  
  
  CONCLUSIONS
  The acceleration of clonal evolution of p210 bcr-abl-transduced 32D myeloid progenitors associated with p53 functional abrogation is consistent with oncosuppressor loss having a key role in CML progression. This would allow emergence of additional genomic aberrations which would lead to the fully transformed phenotype of blast crisis. Deregulated activity of the cyclin B1-cdc2 complex may be involved in the loss of temporal co-ordination of mitotic events and further free the barrier to genomic instability of CML clonal myeloid progenitors lacking p53.
authors.affiliation: Istituto di Ematologia e Oncologia Medica "Lorenzo e Ariosto Seràgnoli", University of Bologna Medical School, Bologna, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Brusa
authors.forename: Michela
authors.initials: M
authors.lastname: Benvenuti
authors.forename: Lucia
authors.initials: L
authors.lastname: Mazzacurati
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Laura
authors.initials: L
authors.lastname: Pattacini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Enza
authors.initials: E
authors.lastname: Barbieri
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D002999:Clone Cells; D019926:Cyclin B / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016678:Genome; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D011003:Ploidies; D011123:Polyploidy; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D019926:Cyclin B; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016203:CDC2 Protein Kinase