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

Jonas De Kesel (UGent) , Igor Fijalkowski (UGent) , Tim Pieters (UGent) , Cristina Borin (UGent) , Kasper Thorhauge Christensen (UGent) , Manou Wittouck (UGent) , Jolien Van Laere (UGent) , Laura Guerrero (UGent) , Lindy Reunes (UGent) , Marino Caruso, et al.
(2025) BLOOD. 146(3). p.275-290
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Abstract
RNA homeostasis is dysregulated in cancer and impacts disease progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic mRNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m6A changes in T-cell acute lymphoblastic leukemia (T-ALL) patient samples 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. Additionally, the levels of the m6A demethylase fat mass and obesity-associated (FTO) are significantly elevated in T-ALL cells compared to 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.
Keywords
ACUTE LYMPHOBLASTIC-LEUKEMIA, MESSENGER-RNA, GLUCOCORTICOID RESISTANCE, PHASE-I, TRANSLATION, INHIBITION, DEMETHYLATION, REGULATORS, MACHINERY, MULTIPLE

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Citation

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MLA
De Kesel, Jonas, et al. “HNRNPC and M6A RNA Methylation Control Oncogenic Transcription and Metabolism in T-Cell Leukemia.” BLOOD, vol. 146, no. 3, 2025, pp. 275–90, doi:10.1182/blood.2024026848.
APA
De Kesel, J., Fijalkowski, I., Pieters, T., Borin, C., Christensen, K. T., Wittouck, M., … Ntziachristos, P. (2025). HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia. BLOOD, 146(3), 275–290. https://doi.org/10.1182/blood.2024026848
Chicago author-date
De Kesel, Jonas, Igor Fijalkowski, Tim Pieters, Cristina Borin, Kasper Thorhauge Christensen, Manou Wittouck, Jolien Van Laere, et al. 2025. “HNRNPC and M6A RNA Methylation Control Oncogenic Transcription and Metabolism in T-Cell Leukemia.” BLOOD 146 (3): 275–90. https://doi.org/10.1182/blood.2024026848.
Chicago author-date (all authors)
De Kesel, Jonas, Igor Fijalkowski, Tim Pieters, Cristina Borin, Kasper Thorhauge Christensen, Manou Wittouck, Jolien Van Laere, Laura Guerrero, Lindy Reunes, Marino Caruso, Bijal Thakkar, Wouter Sleeckx, Luyao Kevin Xu, Filip Van Nieuwerburgh, Dieter Deforce, Kim De Keersmaecker, Tim Lammens, Steven Goossens, Tom Taghon, Cuijuan Han, Giulia Veltri, Valentina Serafin, Bruno Palhais, Nitesh D. Sharma, Hao Huang, Hudan Liu, Ksenia Matlawska-Wasowska, Ana Milovanovic, Eva Maria Novoa, Eric Wang, and Panagiotis Ntziachristos. 2025. “HNRNPC and M6A RNA Methylation Control Oncogenic Transcription and Metabolism in T-Cell Leukemia.” BLOOD 146 (3): 275–290. doi:10.1182/blood.2024026848.
Vancouver
1.
De Kesel J, Fijalkowski I, Pieters T, Borin C, Christensen KT, Wittouck M, et al. HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia. BLOOD. 2025;146(3):275–90.
IEEE
[1]
J. De Kesel et al., “HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia,” BLOOD, vol. 146, no. 3, pp. 275–290, 2025.
@article{01JW1EGF480FB0FK2Q0Z7NG74N,
  abstract     = {{RNA homeostasis is dysregulated in cancer and impacts disease progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic mRNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m6A changes in T-cell acute lymphoblastic leukemia (T-ALL) patient samples 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. Additionally, the levels of the m6A demethylase fat mass and obesity-associated (FTO) are significantly elevated in T-ALL cells compared to 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.}},
  author       = {{De Kesel, Jonas and Fijalkowski, Igor and Pieters, Tim and Borin, Cristina and Christensen, Kasper Thorhauge and Wittouck, Manou and Van Laere, Jolien and Guerrero, Laura and Reunes, Lindy and Caruso, Marino and Thakkar, Bijal and Sleeckx, Wouter and Kevin Xu, Luyao and Van Nieuwerburgh, Filip and Deforce, Dieter and De Keersmaecker, Kim and Lammens, Tim and Goossens, Steven and Taghon, Tom and Han, Cuijuan and Veltri, Giulia and Serafin, Valentina and Palhais, Bruno and Sharma, Nitesh D. and Huang, Hao and Liu, Hudan and Matlawska-Wasowska, Ksenia and Milovanovic, Ana and Novoa, Eva Maria and Wang, Eric and Ntziachristos, Panagiotis}},
  issn         = {{0006-4971}},
  journal      = {{BLOOD}},
  keywords     = {{ACUTE LYMPHOBLASTIC-LEUKEMIA,MESSENGER-RNA,GLUCOCORTICOID RESISTANCE,PHASE-I,TRANSLATION,INHIBITION,DEMETHYLATION,REGULATORS,MACHINERY,MULTIPLE}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{275--290}},
  title        = {{HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia}},
  url          = {{http://doi.org/10.1182/blood.2024026848}},
  volume       = {{146}},
  year         = {{2025}},
}
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