Abstract
AbstractOsteosarcoma is a high-grade bone-forming neoplasm, with a complex genome. Tumours frequently show chromothripsis, many deletions, translocations and copy number alterations. Alterations in the p53 or Rb pathway are the most common genetic alterations identified in osteosarcoma. Using spontaneously transformed murine mesenchymal stem cells (MSCs) which formed sarcoma after subcutaneous injection into mice, it was previously demonstrated that p53 is most often involved in the transformation towards sarcomas with complex genomics, including osteosarcoma. In the current study, not only loss of p53 but also loss of p16Ink4a is shown to be a driver of osteosarcomagenesis: murine MSCs with deficient p15Ink4b, p16Ink4a, or p19Arf transform earlier compared to wild-type murine MSCs. Furthermore, in a panel of nine spontaneously transformed murine MSCs, alterations in p15Ink4b, p16Ink4a, or p19Arf were observed in eight out of nine cases. Alterations in the Rb/p16 pathway could indicate that osteosarcoma cells are vulnerable to CDK4/CDK6 inhibitor treatment. Indeed, using two-dimensional (n = 7) and three-dimensional (n = 3) cultures of human osteosarcoma cell lines, it was shown that osteosarcoma cells with defective p16INK4A are sensitive to the CDK4/CDK6 inhibitor palbociclib after 72-hour treatment. A tissue microarray analysis of 109 primary tumour biopsies revealed a subset of patients (20–23%) with intact Rb, but defective p16 or overexpression of CDK4 and/or CDK6. These patients might benefit from CDK4/CDK6 inhibition, therefore our results are promising and might be translated to the clinic.Osteosarcoma is a tumour with a highly complex genome, which hampers the identification of driver genes. Using a model of murine mesenchymal stem cells (MSCs) with deficient p15Ink4b, p16Ink4a, or p19Arf that transform earlier compared to wild-type MSCs, the authors demonstrated that loss of p16Ink4a is a driver of osteosarcomagenesis. This can be exploited with a CDK4/CDK6 inhibitor, as osteosarcoma cells showed sensitivity to palbociclib which might be used as a novel therapeutic option.
Highlights
Osteosarcoma is the most common malignant mesenchymal tumour of the bone in children and adolescents and characterized by osteoid formation
We previously demonstrated that murine and canine mesenchymal stem cells (MSCs) spontaneously transform in vitro and can be used to model driver or initiating events involved in the development of sarcomas with complex genomics, including osteosarcoma[19]
We showed that spontaneously transformed murine MSCs harbour point mutations in Trp[53] and/or copy number alterations in Cdkn2a and Cdkn2b
Summary
Osteosarcoma is the most common malignant mesenchymal tumour of the bone in children and adolescents and characterized by osteoid formation. The second most common alteration inactivates RB1 (29–47%)[4,5], a tumour suppressor gene controlling cell cycle progression[6]. CDK4 is amplified in 10% of highgrade osteosarcomas, and together with CDK6 directly controls Rb activity by phosphorylation of Rb7–9. Upstream of the Rb pathway, p15INK4B and p16INK4A can inhibit CDK4 and CDK6 activity. P15INK4b is transcribed from the CDKN2B gene, whereas p16INK4A, and its alternate reading frame p14ARF (p19Arf in mouse), is transcribed from the CDKN2A gene (a schematic overview of the locus is depicted in Supplementary Fig. S1). CDKN2B and CDKN2A are adjacent loci on the genome and are often codeleted. Somatic alterations in both genes have been identified in
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
