HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia.
Document Type
Article
Publication Date
7-17-2025
Original Citation
De Kesel J,
Fijalkowski I,
Pieters T,
Borin C,
Christensen K,
Wittouck M,
Van Laere J,
Guerrero L,
Reunes L,
Caruso M,
Thakkar B,
Sleeckx W,
Xu L,
Van Nieuwerburgh F,
Deforce D,
De Keersmaecker K,
Lammens T,
Goossens S,
Taghon T,
Han C,
Veltri G,
Serafin V,
Palhais B,
Sharma N,
Huang H,
Liu H,
Matlawska-Wasowska K,
Milovanovic A,
Novoa E,
Wang E,
Ntziachristos P.
HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia. Blood. 2025;146(3):275-90.
Keywords
JGM, Humans, Adenosine, Methylation, Heterogeneous-Nuclear Ribonucleoprotein Group C, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Transcription, Genetic, Gene Expression Regulation, Leukemic, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, RNA, Messenger, Proto-Oncogene Proteins c-myc, Leukemia, T-Cell, RNA Methylation
JAX Source
Blood. 2025;146(3):275-90.
ISSN
1528-0020
PMID
40435411
DOI
https://doi.org/10.1182/blood.2024026848
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.