MELK promotes chromosomal instability in uterine leiomyosarcoma

Uterine Leiomyosarcoma (ULMS) is the most lethal gynecologic malignancy with few therapeutic options and its exact pathogenic mechanism remains largely unclear. To explore the molecular pathogenesis of the disease, here we performed Whole Genome Sequencing (WGS) and Target Region Sequencing (TRS) and found that the global chromosomal instability (CIN) was much more common than nucleotide alterations. Further transcriptome analysis revealed that many differentially expressed genes involving in pathways of mitosis and cell cycle, and MELK stands out as the most prominent gene. MELK promoted ULMS cell cycle, proliferation, migration and invasion in human leiomyosarcoma. Our study provided evidence that MELK is responsible for phosphorylating MAD2L1 and RB1, resulting in uneven chromosomal distribution in daughter cells and facilitating the progression of the cell cycle. Thus, our study reveals a molecular mechanism of CIN in ULMS and provide potential therapeutic modalities in treating ULMS.