Targeting miR-21 with NL101 blocks c-Myc/Mxd1 loop and inhibits the growth of B cell lymphoma.

NL101 has shown activities against multiple myeloma and acute myeloid leukemia, but its anti-lymphoma activity remains unknown. The transcription factor c-Myc is frequently dysregulated in aggressive B cell lymphomas such as double-hit lymphoma, for which the standard of care is still lacking. A novel approach to target c-Myc needs to be explored. Although the role of oncogenic microRNA-21 (miR-21) was well established in an inducible mice model of B cell lymphoma, whether targeting miR-21 could inhibit the growth of B cell lymphoma and its underlying mechanisms is unclear. We used MTT assay and flow cytometry to determine the inhibitory effect of NL101 on the cell proliferation of B cell lymphoma . The lymphoma xenograft mice models were generated to evaluate the anti-lymphoma function . Western blot and qPCR were applied to measure the expression levels of protein and microRNA, respectively. To investigate the mechanisms of action in NL101, we used genechip to profile differentially-expressed genes upon NL101 induction. Luciferase reporter system and chromatin immunoprecipitation were used for the validation of target gene or miRNA. Nl101 significantly inhibited B cell lymphoma proliferation through induction of cell cycle arrest and apoptosis. NL101 suppressed the growth of B cell lymphoma and prolonged the survival of lymphoma xenograft models. Gene expression profiling revealed that miR-21 was significantly decreased upon the induction of NL101 in B cell lymphoma. The miR-21 level was associated with the sensitivity of NL101. miR-21 inhibited Mxd1 expression via directly combining to Mxd1 3'-UTR; c-Myc activated miR-21 expression by directly binding to the miR-21 promoter. NL101 significantly inhibited the growth of B cell lymphoma and . The novel c-Myc/miR-21/Mxd1 positive-feedback loop is critical for the maintenance of B cell lymphoma survival. Targeting miR-21 to block c-Myc/miR-21/Mxd1 loop represents a novel potential strategy of c-Myc-directed therapy.