HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia
Abstract
Abstract RNA homeostasis is dysregulated in cancer and affects disease progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic messenger RNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m6A changes in patients with T-cell acute lymphoblastic leukemia (T-ALL), to our knowledge, for the first time. It reveals m6A’s regulatory role in the oncogenic MYC and cholesterol biosynthesis pathways. In addition, we discovered that T-ALL is highly dependent on the m6A reader heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC is transcriptionally controlled by MYC and is an essential regulator of m6A-modified transcripts. Consequently, transcriptional silencing of HNRNPC profoundly impairs oncogenic pathways and critically diminishes leukemia cell growth. In addition, the levels of the m6A demethylase fat mass and obesity-associated protein (FTO) are significantly elevated in T-ALL cells compared with normal cells, and to other types of leukemia. Targeting FTO shows therapeutic potential in preclinical disease models and synergizes with clinically relevant therapeutics. Our findings underscore the integral role of RNA methylation in orchestrating cancer cell oncogene expression and metabolism and highlight promising novel therapeutic avenues for the treatment of T-cell leukemia.
Article Details
Authors (31)
Jonas De Kesel
1Ghent University, Ghent, Belgium
Igor Fijalkowski
1Ghent University, Ghent, Belgium
Tim Pieters
1Ghent University, Ghent, Belgium
Cristina Borin
1Ghent University, Ghent, Belgium
Kasper Thorhauge Christensen
1Ghent University, Ghent, Belgium
Manou Wittouck
1Ghent University, Ghent, Belgium
Jolien Van Laere
1Ghent University, Ghent, Belgium
Laura Guerrero
Department of Bioengineering, Stanford University
Lindy Reunes
1Leukemia Therapy Resistance Lab, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Marino Caruso
4Laboratory for Disease Mechanisms in Cancer, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
Bijal Thakkar
1Leukemia Therapy Resistance Lab, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Wouter Sleeckx
Luyao Kevin Xu
1Leukemia Therapy Resistance Lab, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Filip Van Nieuwerburgh
Dieter Deforce
Kim De Keersmaecker
4Laboratory for Disease Mechanisms in Cancer, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
Tim Lammens
Steven Goossens
Tom Taghon
Cuijuan Han
1The Jackson Laboratory, Farmington, United States
Giulia Veltri
3University of Padova, Padova, Italy
Valentina Serafin
4University of Modena and Reggio Emilia, Modena, Italy
Bruno Palhais
1Leukemia Therapy Resistance Lab, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Nitesh D. Sharma
15Department of Pharmacology-Toxicology, University of Alabama at Birmingham, Birmingham, AL
Hao Huang
Hudan Liu
16Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
Ksenia Matlawska-Wasowska
2University of Alabama at Birmingham, Birmingham, United States
Ana Milovanovic
18Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
Eva Maria Novoa
Eric Wang
Panagiotis Ntziachristos
1Ghent University, Ghent, Belgium