Pseudomyogenic Hemangioendothelioma Recapitulated in Endothelial Cells from Human Induced Pluripotent Stem Cells Engineered to Express the SERPINE1-FOSB Translocation

Chromosomal translocations are prevalent among soft tissue tumors including those of the vasculature. Pseudomyogenic hemangioendothelioma (PHE) is one such tumor. It has features of endothelial cells (ECs) and a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but has been difficult to study since to date no cell lines have been derived from the tumor. To address this, we engineered the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiated these into ECs (hiPSC-ECs). Comparison of parental and modified (PHE) lines with the t(7;19)(q22;q13) SERPINE1-FOSB translocation showed (i) elevated expression of FOSB specifically in hiPSC-ECs in vitro and in vivo (ii) increased proliferation and tube formation but decreased endothelial barrier function (iii) transcriptome alterations specific for hiPSC-ECs that reflect typical PHE histopathological features (iv) invasive growth and abnormal vessel formation in mouse after transplantation of the mutated cells. hiPSC-ECs carrying the SERPINE1-FOSB translocation thus recapitulated functional features of PHE and demonstrated that this approach can yield models of translocation-driven tumors for identification of therapeutic targets and deeper understanding of underlying tumorigenic mechanisms.