ROR1-targeted delivery of miR-29b induces cell cycle arrest and therapeutic benefit in vivo in a CLL mouse model
| العنوان: | ROR1-targeted delivery of miR-29b induces cell cycle arrest and therapeutic benefit in vivo in a CLL mouse model |
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| المؤلفون: | Sivasubramanian Baskar, Ralf Bundschuh, Christoph Rader, Logan A. Walker, Rajeswaran Mani, Swagata Goswami, Chi-Ling Chiang, John C. Byrd, X. Mo, Mitch A. Phelps, Xiaomeng Huang, Zhiliang Xie, L. James Lee, Guido Marcucci, Frank Frissora, Natarajan Muthusamy, Pearlly S. Yan |
| المصدر: | Blood |
| بيانات النشر: | American Society of Hematology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Immunoconjugates, Cell cycle checkpoint, Cell Survival, Chronic lymphocytic leukemia, Immunology, Receptor Tyrosine Kinase-like Orphan Receptors, Biochemistry, Theranostic Nanomedicine, Receptor tyrosine kinase, Epigenesis, Genetic, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, hemic and lymphatic diseases, Cell Line, Tumor, Biomarkers, Tumor, medicine, Animals, Humans, Lymphoid Neoplasia, biology, business.industry, Cell Cycle Checkpoints, Cell Biology, Hematology, DNA Methylation, Cell cycle, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Survival Rate, Disease Models, Animal, MicroRNAs, Leukemia, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, ROR1, Cancer research, biology.protein, Nanoparticles, business, Reprogramming |
| الوصف: | Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1+ CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eμ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell–targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1+ B-cell malignancies. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ae0b5bc86ee98658605fe3fd7504cb0Test https://doi.org/10.1182/blood.2018882290Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4ae0b5bc86ee98658605fe3fd7504cb0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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