Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology

• Published in: Laboratory investigation 2019-09, Vol.99 (9), p.1309-1320
• Main Authors: Kim, Yu Jin, Kim, Mingi, Park, Hyung Kyu, Yu, Dan Bi, Jung, Kyungsoo, Song, Kyoung, Choi, Yoon-La
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/31; 13/51; 14/63; 42/44; 45/77; 631/67/1798; 631/67/1857; 64/60; 82/80; Animal models; Animals; Bone marrow; c-Myc protein; Cell Dedifferentiation - genetics; Cell migration; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Cytology; Deactivation; Depletion; Diagnostic systems; Genetic factors; Heterografts; Humans; Inactivation; Laboratory Medicine; Liposarcoma; Liposarcoma - genetics; Liposarcoma - metabolism; Liposarcoma - pathology; MDM2 protein; Medicine; Medicine & Public Health; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Morphology; Mutation; Myc protein; p53 Protein; Pathology; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Sarcoma; Stem cell transplantation; Stem cells; Telomerase reverse transcriptase; Tumorigenesis; Ubiquitin-protein ligase; Xenografts; Xenotransplantation
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-019-0263-4

Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria for well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that the depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis remains unclear. We examined whether MDM2 and/or CDK4 cause WDLPS/DDLPS, using two types of transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that the co-overexpression of MDM2 and CDK4 plays a key role in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency when compared with the sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that the co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can cause proliferative sarcoma with a DDLPS-like morphology in vivo. Our results suggest that the co-overexpression of MDM2 and CDK4, along with multiple genetic factors, increases the tendency for high-grade sarcoma with a DDLPS-like morphology in transformed human BMSCs by accelerating their growth and migration and blocking their adipogenic potential.