Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia
Abstract
Abstract N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.
Article Details
Authors (36)
Lili Ren
Honghai Zhang
Olga Bobileva
4Latvian Institute of Organic Synthesis, Riga, Latvia
Francesco Nai
5Department of Biochemistry, University of Zurich, Zurich, Switzerland
Hongjie Bi
Anthony Chan
Genevieve E. Baker
6Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA
Lei Dong
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
David Guarin
8Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX
Weidong Hu
Wei Li
Irena Leite
4Latvian Institute of Organic Synthesis, Riga, Latvia
Xueer Wang
Xiaoxu Zhang
State Key Laboratory of Photoelectric Conversion and Utilization of Solar Energy, Qingdao New Energy Shandong Laboratory, Qingdao Institute of Bioenergy and Bioprocess Technology
Meilin Xue
Haixia Wang
Hanjun Qin
Xiwei Wu
Lucy Ghoda
Lin Xu
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Bin Zhang
Ling Li
Mark Wunderlich
James C. Mulloy
Courtney L. Jones
12Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Seán E. O’Leary
13Department of Biochemistry, University of California Riverside, Riverside, CA
Hongzhi Li
Steven T. Rosen
Chun-Wei David Chen
1Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA
Nora Heisterkamp
J. Jefferson P. Perry
6Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA
Yunsun Nam
Jianjun Chen
State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment
Amedeo Caflisch
Xiaobo Li
Rui Su