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

Abstract

Background: 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. Methods: We used MTT assay and flow cytometry to determine the inhibitory effect of NL101 on the cell proliferation of B cell lymphoma in vitro. The lymphoma xenograft mice models were generated to evaluate the anti-lymphoma function in vivo. 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. Results: Nl101 significantly inhibited B cell lymphoma proliferation through induction of cell cycle arrest and apoptosis. NL101 suppressed the growth of B cell lymphoma in vivo 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. Conclusion: NL101 significantly inhibited the growth of B cell lymphoma in vitro and in vivo. 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.

• Authors: Shu Li, Xin He, Yichao Gan, Jiawei Zhang, Feiqiong Gao, Limin Lin, Xi Qiu, Teng Yu, Xuzhao Zhang, Panpan Chen, Jiefeng Tong, Wenbin Qian, Yang Xu
• Journal: Theranostics (Theranostics) Vol. 11 Issue 7 Pg. 3439-3451 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33537096 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antineoplastic Agents, Alkylating
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• MIRN21 microRNA, human
• MXD1 protein, human
• MYC protein, human
• MicroRNAs
• NL-101
• Proto-Oncogene Proteins c-myc
• Repressor Proteins
• Vorinostat
• Bendamustine Hydrochloride

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Apoptosis (drug effects, genetics)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Bendamustine Hydrochloride (pharmacology)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphoma, B-Cell (drug therapy, genetics, mortality, pathology)
• Mice
• Mice, Inbred NOD
• MicroRNAs (genetics, metabolism)
• Molecular Targeted Therapy
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Survival Analysis
• Tumor Burden (drug effects)
• Vorinostat (pharmacology)
• Xenograft Model Antitumor Assays