PPARγ agonists enhance ET743 - induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differen tiation based response to ET743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS: CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET743. ET743 downregulated TLS:CHOP expression, which correlated with CEBP α expression and adipocytic differentiation. Furthermore, PPAR £ agonists enhanced the differentiation process initiated by ET743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET743 plus PPAR £ agonists, for the treatment of MRCLS.