RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

被引：276

作者：

Shen, Chao ^{[1
]}

Sheng, Yue ^{[2
,3
]}

Zhu, Allen C. ^{[4
]}

Robinson, Sean ^{[1
]}

Jiang, Xi ^{[1
,5
,6
,7
]}

Dong, Lei ^{[1
]}

Chen, Huiying ^{[1
]}

Su, Rui ^{[1
]}

Yin, Zhe ^{[1
,8
]}

Li, Wei ^{[1
]}

Deng, Xiaolan ^{[1
]}

Chen, Yinhuai ^{[9
,10
]}

Hu, Yueh-Chiang ^{[9
,10
]}

Weng, Hengyou ^{[1
]}

Huang, Huilin ^{[1
]}

Prince, Emily ^{[1
]}

Cogle, Christopher R. ^{[2
,3
]}

Sun, Miao ^{[10
,11
]}

Zhang, Bin ^{[12
]}

Chen, Chun-Wei ^{[1
]}

Marcucci, Guido ^{[12
]}

He, Chuan ^{[4
]}

Qian, Zhijian ^{[2
,3
]}

Chen, Jianjun ^{[1
]}

机构：

[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Monrovia, CA 91016 USA

[2] Univ Florida, Dept Med, Gainesville, FL 32608 USA

[3] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32608 USA

[4] Univ Chicago, Howard Hughes Med Inst, Med Scientist Training Program,Comm Canc Biol, Dept Chem,Dept Biochem & Mol Biol,Inst Biophys Dy, 5841 S Maryland Ave, Chicago, IL 60637 USA

[5] Zhejiang Univ, Inst Hematol, Sch Med, Dept Pharmacol,Affiliated Hosp 1, Hangzhou 310058, Zhejiang, Peoples R China

[6] Zhejiang Univ, Inst Hematol, Bone Marrow Transplantat Ctr, Sch Med,Affiliated Hosp 1, Hangzhou 310058, Zhejiang, Peoples R China

[7] Zhejiang Engn Lab Stem Cell & Immunotherapy, Hangzhou 310058, Zhejiang, Peoples R China

[8] Chongqing Canc Hosp, Dept Thorac Surg, Chongqing 400030, Peoples R China

[9] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Transgen Anim & Genome Editing Facil, Cincinnati, OH 45229 USA

[10] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA

[11] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[12] City Hope Natl Med Ctr, Beckman Res Inst, Dept Hematol Malignancies Translat Sci, Monrovia, CA 91016 USA

来源：

CELL STEM CELL | 2020年 / 27卷 / 01期

基金：

美国国家卫生研究院;

关键词：

ACIDIC COILED-COIL; N-6-METHYLADENOSINE MODIFICATION; HEMATOPOIETIC STEM; PROTEIN TACC3; NUCLEAR-RNA; EXPRESSION; TARGET; N6-METHYLADENOSINE; DIFFERENTIATION; CRISPR-CAS9;

D O I：

10.1016/j.stem.2020.04.009

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

N-6-methyladenosine (m(6)A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m(6)A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m(6)A axis.

引用

页码：64 / +

页数：26

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