KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition

Author:

Xu Jing1,Zhong Ailing1,Zhang Shan1,Chen Mei1,Zhang Lanxin1,Hang Xiaohang1,Zheng Jianan1,Wu Baohong1,Deng Xintong1,Pan Xiangyu1,Wang Zhongwang1,Qi Lu1,Shi Kaidou1,Li Shujun1,Wang Yiyun1,Wang Manli1,Chen Xuelan1,Zhang Qi1,Liu Pengpeng1,Gale Robert Peter23,Chen Chong1,Liu Yu1ORCID,Niu Ting1

Affiliation:

1. Department of Hematology Institute of Hematology State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China

2. Centre for Hematology Imperial College of Science Technology and Medicine London SW7 2BX UK

3. Department of Hematologic Oncology Sun Yat‐sen Cancer Center Guangzhou 510060 China

Abstract

AbstractKMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX‐5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.

Funder

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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