miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

被引：133

作者：

Li, Zejuan ^{[1
]}

Huang, Hao ^{[1
]}

Chen, Ping ^{[1
]}

He, Miao ^{[1
,7
]}

Li, Yuanyuan ^{[1
]}

Arnovitz, Stephen ^{[1
]}

Jiang, Xi ^{[1
]}

He, Chunjiang ^{[1
]}

Hyjek, Elizabeth ^{[2
]}

Zhang, Jun ^{[3
]}

Zhang, Zhiyu ^{[4
]}

Elkahloun, Abdel ^{[5
]}

Cao, Donglin ^{[1
,8
]}

Shen, Chen ^{[1
]}

Wunderlich, Mark ^{[6
]}

Wang, Yungui ^{[9
]}

Neilly, Mary Beth ^{[1
]}

Jin, Jie ^{[9
]}

Wei, Minjie ^{[7
]}

Lu, Jun ^{[10
]}

Valk, Peter J. M. ^{[11
]}

Delwel, Ruud ^{[11
]}

Lowenberg, Bob ^{[11
]}

Le Beau, Michelle M. ^{[1
]}

Vardiman, James ^{[2
]}

Mulloy, James C. ^{[6
]}

Zeleznik-Le, Nancy J. ^{[12
]}

Liu, Paul P. ^{[5
]}

Zhang, Jiwang ^{[3
]}

Chen, Jianjun ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[3] Loyola Univ, Inst Oncol, Cardinal Bernardin Canc Ctr, Med Ctr, Maywood, IL 60153 USA

[4] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA

[5] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA

[6] Univ Cincinnati, Div Expt Hematol & Canc Biol, Cincinnati Childrens Hosp, Med Ctr,Coll Med, Cincinnati, OH 45229 USA

[7] China Med Univ, Dept Pharmacol, Shenyang 110001, Liaoning, Peoples R China

[8] Guangdong 2 Prov People s Hosp, Dept Lab Med, Guangzhou 510317, Guangdong, Peoples R China

[9] Zhejiang Univ, Inst Hematol, Affiliated Hosp 1, Coll Med, Hangzhou 310058, Zhejiang, Peoples R China

[10] Yale Univ, Dept Genet, Yale Stem Cell Ctr, New Haven, CT 06520 USA

[11] Erasmus Univ, Dept Hematol, Med Ctr, NL-3000 CA Rotterdam, Netherlands

[12] Loyola Univ, Med Ctr, Dept Med, Maywood, IL 60153 USA

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION PROFILE; MESSENGER-RNA; HISTONE MODIFICATIONS; MICRORNAS; CELLS; HOXA9; MEIS1; STEM;

D O I：

10.1038/ncomms1681

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL -rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL -rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

引用

页数：12

共 60 条

[1] MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia [J].