HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia

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.

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Journal
Blood
Published
2025-05-28
DOI
https://doi.org/10.1182/blood.2024026848
Citations
9
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
7.25
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article

HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia

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9 citations
Blood
RNA modifications and cancer
7.25
article

HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia

Tom Taghon, Steven Goossens, Lindy Reunes, Nitesh Sharma, Tim Lammens, Cristina Borin, Panagiotis Ntziachristos, Jolien Van Laere, Tim Pieters, Igor Fijałkowski, Marino Caruso, Cuijuan Han, Bijal Thakkar, Wouter Sleeckx, Kasper Thorhauge Christensen, Laura Ruy Sanchez Guerrero, Valentina Serafin, Giulia Veltri, Ksenia Matlawska‐Wasowska, Dieter Deforce, Bruno Palhais, Jonas De Kesel, Hudan Liu, Kim De Keersmaecker, Filip Van Nieuwerburgh, Eric Wang, Hao Huang, Eva Nóvoa, Luyao Xu, Ana Milovanovic, Manou Wittouck
article en
9 citations

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.

BloodVol. 146(3)
University of Modena and Reggio Emilia (IT), HOGENT University of Applied Sciences and Arts (BE), University of Padua (IT), Universitat Pompeu Fabra (ES), Ghent University Hospital (BE), University of Alabama at Birmingham (US), Ghent University (BE), Wuhan University (CN), AstraZeneca (South Korea) (KR), VIB-KU Leuven Center for Cancer Biology (BE), Jackson Laboratory (US), Cancer Research Institute Ghent (BE), Zhongnan Hospital of Wuhan University (CN), Centre for Genomic Regulation (ES), Pharmaceutical Biotechnology (Czechia) (CZ), Città della Speranza Foundation (IT), Wuhan University of Science and Technology (CN), KU Leuven (BE)
Good health and well-being
Openalex Percentile: Top 3%
RNA modifications and cancer
7.25
DOIOpen Access PDFOpenAlex
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