Selective elimination of amplified CDK4 sequences correlates with spontaneous adipocytic differentiation in liposarcoma.
Well-differentiated and undifferentiated liposarcomas are characterized by high-level amplifications of chromosome 12 regions including the CDK4 and MDM2 genes. These amplicons are either localized, in well-differentiated liposarcoma (WDLPS), on extrachromosomal structures (ring or rod chromosomes), or integrated into chromosome arms in undifferentiated tumors. Our results reveal that extrachromosomal amplicons are unstable, and frequently lost by micronucleation. This loss correlates with hypermethylation of eliminated sequences and changes of their replication time. Treatment of cells with demethylating agents during early S-phase significantly decreases the rate of micronuclei positive for CDK4. We also demonstrate that, in our model, micronuclei are generated during anaphase as a consequence of anaphase abnormalities (chromosome lagging and anaphase bridges). Finally, a dramatic increase of adipocytic differentiation was noted in cells that have eliminated copies of CDK4 gene in micronuclei. These findings provide evidence that, in WDLPS, adipocytic differentiation could be the consequence of CDK4 loss, an event occurring rarely in undifferentiated tumors in which the amplified sequences are integrated into chromosome arms.
Hélias-Rodzewicz
Zofia
Z
Institut Curie, Genetics and Biology of Cancers, 26 rue d'Ulm, 75248 Paris cedex 05, France.
Pédeutour
Florence
F
Coindre
Jean-Michel
JM
Terrier
Philippe
P
Aurias
Alain
A
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000705:Anaphase; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002503:Centromere; D018385:Centrosome; D002869:Chromosome Aberrations; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D008080:Liposarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D048629:Micronuclei, Chromosome-Defective; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4