Theranostics 2021; 11(7):3439-3451. doi:10.7150/thno.53561

Research Paper

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

Shu Li1,2, Xin He1,3, Yichao Gan1,4, Jiawei Zhang1,2, Feiqiong Gao1, Limin Lin1,2, Xi Qiu1, Teng Yu1, Xuzhao Zhang1, Panpan Chen1, Jiefeng Tong1, Wenbin Qian1,5, Yang Xu1,5,6✉

1. Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
2. Zhejiang University Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
3. Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010.
4. Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, China.
5. National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
6. Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.

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Citation:
Li S, He X, Gan Y, Zhang J, Gao F, Lin L, Qiu X, Yu T, Zhang X, Chen P, Tong J, Qian W, Xu Y. Targeting miR-21 with NL101 blocks c-Myc/Mxd1 loop and inhibits the growth of B cell lymphoma. Theranostics 2021; 11(7):3439-3451. doi:10.7150/thno.53561. Available from https://www.thno.org/v11p3439.htm

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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.

Keywords: B cell lymphoma, miR-21, NL101, c-Myc, Mxd1