Therapeutic application of the tumour suppressive miR-193b in Acute Myeloid Leukaemia

Dysregulation of microRNAs (miRNAs) is a hallmark of leukaemogenises. Many miRNAs regulate leukaemic cell proliferation by modulating several kinases or interfering with the expression of key proto-oncogenes. miR-193b expression is globally downregualted in Acute Myeloid Leukaemia (AML) and we found that low endogenous level of miR-193b is an independent marker for poor prognosis in adult and paediatric AML. Restoring the expression of miR-193b might provide a therapeutic window. Ectopic lentiviral expression of miR-193b or transient induction of miR-193b mimics reduced CCND1 expression, induced G1 cell cycle arrest and triggered apoptosis in various AML cell lines and patient blasts in vitro. The regulatory mechanism of miR-193b was found to be driven by targeting several components of MAPK pathway including the KIT/RAS/RAF/MEK/ERK cascade. We are developing a lipid nanoparticle based delivery system to restore the tumour suppressor activity of miR-193b in AML patient derived xenografts in vivo and exploiting this therapeutic intervention with current AML treatment.