MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA

被引:58
作者
Bousquet, Marina [1 ]
Diu Nguyen [1 ]
Chen, Cynthia [1 ]
Shields, Lauren [1 ]
Lodish, Harvey F. [1 ,2 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] MIT, Dept Biol, Cambridge, MA USA
来源
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2012年 / 97卷 / 11期
关键词
miR-125b; myeloid differentiation; apoptosis; proliferation; CBFB; ABTB1; HEMATOPOIETIC STEM-CELLS; CORE-BINDING-FACTOR; TUMOR-SUPPRESSOR; CANCER CELLS; CBF-BETA; MIR-125B; LEUKEMIA; EXPRESSION; GENE; DIFFERENTIATION;
D O I
10.3324/haematol.2011.061515
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 over-expressing 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.
引用
收藏
页码:1713 / 1721
页数:9
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