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

• Published in: Advanced science Vol. 10; no. 19; pp. e2206098 - n/a
• Main Authors: Xu, Jing, Zhong, Ailing, Zhang, Shan, Chen, Mei, Zhang, Lanxin, Hang, Xiaohang, Zheng, Jianan, Wu, Baohong, Deng, Xintong, Pan, Xiangyu, Wang, Zhongwang, Qi, Lu, Shi, Kaidou, Li, Shujun, Wang, Yiyun, Wang, Manli, Chen, Xuelan, Zhang, Qi, Liu, Pengpeng, Gale, Robert Peter, Chen, Chong, Liu, Yu, Niu, Ting
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc; Wiley
• Subjects: acute myeloid leukemia; Animals; Biosynthesis; Blood; Bone marrow; Cancer; CRISPR; Epigenetics; Genes, Tumor Suppressor; Hemoglobin; Humans; KMT2D; Leukemia; Leukemia, Myeloid, Acute - metabolism; Leukocytes; Medical prognosis; Metabolism; Mice; mTOR; Mutation; Proteins; ribosome biogenesis; Ribosomes - genetics; Ribosomes - metabolism; Ribosomes - pathology; RNA, Small Interfering - metabolism; Spleen; TOR Serine-Threonine Kinases - metabolism; Transplants & implants; mTOR; KMT2D; acute myeloid leukemia; epigenetics; ribosome biogenesis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202206098

KMT2C 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. KMT2D is identified as a tumor suppressor gene in acute myeloid leukemia. KMT2D deficiency reduces H3K4 methylation levels and suppresses the expression of DDIT4, the negative regulator in the mTOR signaling pathway, which leads to the activation of the mTOR pathway and enhancement of ribosome biogenesis. KMT2D‐deficient cells are vulnerable to ribosome biogenesis inhibitors such as CX‐5461.