Abstract
SummaryChromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.
Highlights
Chromosomal translocations and their corresponding gene fusions are common in neoplasia and are important in the initiation of tumorigenesis.[1]
We showed that human induced pluripotent stem cells (hiPSCs)-endothelial cell (EC) with the SERPINE1-FOSB fusion were distinct from their isogenic controls and exhibited phenotypic and transcriptomic characteristics very similar to Pseudomyogenic hemangioendothelioma (PHE)
We generated a fusion between intron 1 of SERPINE1 and intron 1 of FOSB, which leads to the same novel start codon as found in PHE tumors from patients (Figure 1A)
Summary
Chromosomal translocations and their corresponding gene fusions are common in neoplasia and are important in the initiation of tumorigenesis.[1]. Pseudomyogenic hemangioendothelioma (PHE) is a rare soft tissue tumor characterized by a specific recurrent balanced translocation, t(7;19)(q22;q13), which fuses SERPINE1 to FOSB.[3,4] The translocation leads to the loss of the first exon of FOSB containing the start codon, resulting in a novel start codon in exon 2 of FOSB. The translocation causes the loss of 48 amino acids at the start of the FOSB protein, which falls under the control of the SERPINE1 promoter.[4] PHE is locally aggressive, rarely metastasizing, and often affecting young adults, especially men between 20 and 50 years of age. The translocation results in the overexpression of FOSB protein in patient tumor samples.[6] PHE does not form functional blood vessels, vascular markers are expressed, suggesting that PHE arises from endothelial cells (ECs) or their precursors. The tumor is defined as an endothelial neoplasm in the 2020 World Health Organization (WHO) classification and classified among the group of vascular tumors.[5,7,8]
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