Therapeutic and prognostic value of miR-193b in AML
Since their discovery several decades ago, microRNAs (miRNAs) have become recognized for their roles as master regulators of gene expression. The ability of a single miRNA to modulate multiple targets allows miRNAs to orchestrate individual pathways at multiple levels or many pathways at once. Accordingly, many miRNAs play crucial roles in developmental, physiologic, and pathological processes. Our group previously showed that miR-193b acts as a negative regulator of hematopoietic stem and progenitor cell physiology, and now we have also elucidated its role in acute myeloid leukemia (AML). The findings have been published in the Journal of Clinical Oncology, in the paper “Endogenous tumor suppressor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia“.
The authors profiled miR-193b-5p/3p expression in 161 pediatric AML patient samples, with a validation cohort of 187 adult AML patients. MiR-193b-3p was found to be downregulated in several cytogenetic subgroups of pediatric and adult AML, and further, low expression served as an independent indicator of poor prognosis in pediatric AML. In knockout mice, miR-193b loss cooperated with Hoxa9/Meis1 during leukemogenesis, while re-expression of miR-193b impaired leukemia engraftment. Likewise, inducing miR-193b in patient-derived AML blasts inhibited leukemic cell growth in vitro and in murine xenografts. The authors went on to investigate the mechanisms through which miR-193b exerts its tumor-suppresive functions, and identified miR-193b targets in the notorious KIT-RAS-RAF-MEK-ERK (MAPK) pathway that is frequently dysregulated in cancer. MiR-193b induces apoptosis and cell cycle arrest by targeting multiple components of the MAPK signalling cascade and the downstream cell cycle regulator CCND1.
In conclusion, miR-193b is a promising biomarker for AML prognosis. Moreover, given the strong its strong tumor-suppressive effect and ability to target multiple hubs of leukemic MAPK signalling simultaneously, we are optimistic about developing miR-193b for future clinical use against AML.