Transcriptome-wide targets of the RNA-binding protein MSI2 and its role in IL-6 signaling

The RNA-binding protein Musashi 2 (MSI2) is emerging to be an important regulator in cancer initiation, progression and drug resistance. Translocations and deregulation of this protein are diagnostic of certain cancers including Chronic Myeloid Leukemia (CML) t(7;17), Acute Myeloid Leukemia (AML) t(10;17), and B-cell Acute Lymphoblastic Leukemia (B-ALL).. In order to understand the function of MSI2 in leukemia, the bound and regulated mRNA targets and their RNA-binding sites need to be identified. Therefore we have applied PAR-CLIP on MSI2 to identify the RNA-binding sites within its regulatory targets and consensus RNA recognition element (RRE). Knockdown of MSI2 altered the expression of several genes with roles in eIF2, HGF, EGF signaling pathways. We also show that MSI2 regulated classic IL (Interleukin)-6 signaling by supporting the degradation of the mRNA of IL-6 signal transducer (IL6ST or GP130) which in turn affected the phosphorylation status of STAT3 and MAPK (ERK). Analysis of public AML patient datasets also revealed lower IL6ST expression in patients with high MSI2 expression and vice versa.