The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development

Abstract

Increasing evidence suggests that mesenchymal stem/stromal cells (MSCs) carrying specific mutations are at the origin of some sarcomas. We have reported that the deficiency of p53 alone or in combination with Rb (Rb(-/-) p53(-/-)) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53(-/-) and Rb(-/-)p53(-/-) MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53(-/-) and Rb(-/-)p53(-/-) ASCs. In addition, gene expression profiling revealed transcriptome similarities between p53- or Rb-p53-deficient BM-MSCs/ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem to determine the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate toward the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors, which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development.

Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

“…5B). To get insight into the biologic functions affected by differentially expressed genes, we used Gorilla software (38)(39)(40) to perform GO analysis comparing KRAS-mutated versus KRAS nonmutated t(4;11) þ patients.…”

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

“…[11][12][13] Mesenchymal stem cells (MSCs) that acquire mutations in oncogenes/TSGs such as p53 may function as tumor-initiating cells leading to de-novo sarcomagensis. [14][15][16][17] Furthermore, MSCs isolated from young mice, aged in culture acquired clinically relevant p53 mutations. 18 In all, these findings suggest a link between p53 inactivation in SCs and tumorigenesis.…”

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…Of these, 196 (61%) were upregulated and 127 (39%) downregulated in lenalidomide-treated AML cells, establishing a lenaledomide-specific transcriptomic signature. To get insights into the biological functions affected by differentially expressed genes, we used the Gorilla software, 30,31 and found that many significant biological processes predicted to be activated in the lenalidomide-treated AML cells were associated with “migration/motility/mobilization/chemotaxis” (Figure 6A). In contrast, exposure of CB-CD34 + HSPCs to lenalidomide did not affect such biological functions (Figure 6B).…”

“…Hierarchical clustering of genes was performed with the one minus correlation metric and the unweighted average distance. Only genes showing >1.5-fold change expression and p-value<0.05 were considered differentially expressed and were subjected to gene ontology (GO) term analysis using Gorilla 30,31 publicly available at http://cbl-gorilla.cs.technion.ac.il. Microarray data were deposited in the public Gene Expression Omnibus database, accession number GSE106748.…”