MYBL2 amplification and expression associate with mitotic activation and prognostic divergence in uterine leiomyosarcoma

Abstract Uterine leiomyosarcoma (uLMS) is an aggressive gynecologic malignancy with limited treatment options. MYBL2, a master regulator of cell-cycle progression, is implicated in several cancers but poorly defined in uLMS. Using multi-omics profiling of 87 fresh-frozen uterine tissues, an integrated mRNA cohort of 201 samples, and immunohistochemistry (IHC) in 133 gynecologic tumors, we show that MYBL2 is focally amplified at 20q13.12 in 30% of uLMS and overexpressed at the mRNA level across cohorts. MYBL2-high tumors show activation of DNA-replication and mitotic pathways, coordinated upregulation of protein targets (CDK1, BIRC5, KPNA2, CCNB1, KIF20A), and an immune-cold microenvironment. Despite consistent mRNA elevation, MYBL2 protein was only sporadically detected, and within the active MMB/DREAM program MYBL2 and FOXM1 were the least-detectable proteins, indicating post-transcriptional suppression of the regulators. Higher MYBL2 mRNA and MMB/DREAM transcriptional activity were associated with shorter overall survival (continuous HR = 4.3 per SD, p = 0.001), whereas higher MYBL2 protein by IHC was associated with longer survival (HR = 0.79, p = 0.046). MYBL2 amplification and overexpression thus define a proliferative, immune-cold, poor-prognosis uLMS subset, with a notable transcript–protein prognostic discordance.