Because of their immunomodulatory properties, human bone marrow stromal cells (hBMSCs) represent promising stem cells for treatment of immune disorders. hBMSCs expansion precedes their clinical use, so the possibility that hBMSCs undergo spontaneous transformation upon long-term culture should be addressed. Whether hBMSCs retain immunosuppressive and anti-inflammatory properties upon oncogenic transformation remains unknown. Using sequentially mutated hBMSCs and spontaneously transformed hBMSCs, we report that, upon oncogenic transformation, hBMSCs lose immunosuppressive and anti-inflammatory properties in vitro and in vivo. Transcriptome profiling and functional assays reveal immune effectors underlying the loss of immunomodulation in transformed hBMSCs. They display a proinflammatory transcriptomic signature, with deregulation of immune and inflammatory modulators and regulators of the prostaglandin synthesis. Transformed hBMSCs lose their capacity to secrete the immunosuppressive prostacyclins prostaglandin E2 (PGE2) and PGI2 but produce proinflammatory thromboxanes. Together, the immunoregulatory profile adopted by hBMSCs largely depends on intrinsic genetic-molecular determinants triggered by genomic instability/oncogenic transformation. ; ISCIII/FEDER (PI10/00449 to P.M., CP11/00024—Miguel Servet—to R.R. and RTICC [RD12/0036/0015]), Excellence Grants from Junta de Andalucia (to M.D.), MINECO (SAF2013-43065 to P.M. and SAF2013-42946-R to R.R.), The Spanish Association Against Cancer and Fundacio´n Sandra Ibarra (to P.M.), Health Canada (to P.M. and M.R.-M.), Grupo Espan˜ol de Investigacio´n en Sarcomas (J.M. Buesa-2012; to R.R.), and Obra Social Cajastur-IUOPA and Gobierno de Asturias (COF13-007; to R.R.). Q.P. was supported by the Netherlands Organization for Scientific Research (NWO/ ZonMw) for a VENI grant (no. 916-13-032). P.M. also acknowledges the financial support from the Obra Social La Caixa-Fundacio` Josep Carreras. ; Peer reviewed