MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA
Background: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125...
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| Format: | Article |
| Language: | en_US |
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Ferrata Storti Foundation
2013
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| Online Access: | http://hdl.handle.net/1721.1/79831 https://orcid.org/0000-0002-7029-7415 |
| _version_ | 1826199115358273536 |
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| author | Bousquet, Marina Nguyen, Diu Chen, Cynthia Shields, Lauren Lodish, Harvey F |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bousquet, Marina Nguyen, Diu Chen, Cynthia Shields, Lauren Lodish, Harvey F |
| author_sort | Bousquet, Marina |
| collection | MIT |
| description | Background: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b.
Design and Methods: To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b.
Results: We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1.
Conclusions: This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1. |
| first_indexed | 2024-09-23T11:14:58Z |
| format | Article |
| id | mit-1721.1/79831 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:14:58Z |
| publishDate | 2013 |
| publisher | Ferrata Storti Foundation |
| record_format | dspace |
| spelling | mit-1721.1/798312022-10-01T02:19:33Z MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA Bousquet, Marina Nguyen, Diu Chen, Cynthia Shields, Lauren Lodish, Harvey F Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Lodish, Harvey F. Marina Bousquet Nguyen, Diu Chen, Cynthia Shields, Lauren Background: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b. Design and Methods: To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b. Results: We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1. Conclusions: This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1. Leukemia & Lymphoma Society of America National Institutes of Health (U.S.) (NIH grant DK068348) National Institutes of Health (U.S.) (NIH grant 5P01 HL066105) 2013-08-12T18:31:58Z 2013-08-12T18:31:58Z 2012-06 2012-04 Article http://purl.org/eprint/type/JournalArticle 0390-6078 1592-8721 http://hdl.handle.net/1721.1/79831 Bousquet, M., D. Nguyen, C. Chen, L. Shields, and H. F. Lodish. MicroRNA-125b Transforms Myeloid Cell Lines by Repressing Multiple mRNA. Haematologica 97, no. 11 (November 2, 2012): 1713-1721. https://orcid.org/0000-0002-7029-7415 en_US http://dx.doi.org/10.3324/haematol.2011.061515 Haematologica Creative Commons Attribution 3.0 http://creativecommons.org/licenses/by/3.0/ application/pdf Ferrata Storti Foundation Ferrata Storti Foundation |
| spellingShingle | Bousquet, Marina Nguyen, Diu Chen, Cynthia Shields, Lauren Lodish, Harvey F MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title | MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title_full | MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title_fullStr | MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title_full_unstemmed | MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title_short | MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA |
| title_sort | microrna 125b transforms myeloid cell lines by repressing multiple mrna |
| url | http://hdl.handle.net/1721.1/79831 https://orcid.org/0000-0002-7029-7415 |
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