Identification of NOTCH-driven matrisome-associated genes as prognostic indicators of multiple myeloma patient survival

Multiple myeloma (MM) provides a permissive tumor microenvironment (TME), supporting tumor cell growth and dissemination, and conferring therapy resistance. RNAseq in the human MM cell lines RPMI 8226 and MM.1S after knockdown of NOTCH1 (N1) and NOTCH2 (N2) was performed to identify genes and pathways that are specifically regulated through NOTCH signaling and contribute to the permissive TME. GSEA confirmed previous findings that NOTCH signaling stimulates the expression of cytokines involved in inflammation, defining an immunosuppressive TME promoting cell viability and migration in MM. Furthermore, a downregulation of “receptor signaling pathway via JAK-STAT” after N1 or N2 knockdown and “regulation of bone resorption” and “regulation of bone remodeling” after N1 knockdown was found. Moreover, our results showed that the expression of multiple core matrisome and matrisome-associated proteins was altered, revealing N1 and N2 as key regulators of extracellular matrix (ECM) remodeling in the bone marrow niche. This process destroys the ECM abundance and integrity and has prognostic relevance. The identification of novel ECM targets will help to develop new treatment strategies that preserve the ECM in a less permissive niche. Overall design: RNA-seq of MM.1S and RPMI-8226 cells with a shRNA mediated knockdown of Notch1 or Notch2 were performed to identify Notch target genes and genes regulated by the Notch pathway.