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

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Jing Xu, Ailing Zhong, Shan Zhang, Mei Chen, Lanxin Zhang, Xiaohang Hang, Jianan Zheng, Baohong Wu, Xintong Deng, Xiangyu Pan, Zhongwang Wang, Lu Qi, Kaidou Shi, Shujun Li, Yiyun Wang, Manli Wang, Xuelan Chen, Qi Zhang, Pengpeng Liu, Robert Peter Gale, Chong Chen, Yu Liu, Ting Niu

TLDR

  • KMT2D is a gene that helps make a protein called ribosomes. These ribosomes are important for making proteins that our body needs. In acute myeloid leukemia (AML), KMT2D is often missing or not working properly. The study found that when KMT2D is missing, it can cause more ribosomes to be made, which can lead to more proteins being made. The study also found that when KMT2D is missing, it can activate a pathway called mTOR, which can help cancer cells grow. The study found that a drug called CX-5461 can stop the growth of cancer cells when KMT2D is missing. The study showed that KMT2D is important for preventing cancer and that it can be targeted with drugs to stop cancer from growing.

Abstract

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.

Overview

  • The study investigates the role of KMT2D in acute myeloid leukemia (AML).
  • KMT2D is downregulated or mutated in AML and its deficiency accelerates leukemogenesis in mice. The study aims to validate KMT2D as a tumor suppressor in AML and reveal its vulnerability to ribosome biogenesis inhibition.

Comparative Analysis & Findings

  • KMT2D deficiency leads to enhanced ribosome biogenesis and increased rRNA and protein synthesis rates in AML cells. The study found that KMT2D deficiency activates the mTOR pathway in both mouse and human AML cells. 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.

Implications and Future Directions

  • The study validates KMT2D as a tumor suppressor in AML and reveals its vulnerability to ribosome biogenesis inhibition. Future research could explore the use of ribosome biogenesis inhibitors as a therapeutic strategy for AML with KMT2D deficiency.
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