m⁶A meets T-ALL: HNRNPC and FTO as new therapeutic targets Free

In this issue of Blood, De Kesel et al reveal widespread alterations in N6-methyladenosine (m⁶A) RNA methylation in T-cell acute lymphoblastic leukemia (T-ALL), identifying heterogeneous nuclear ribonucleoprotein C (HNRNPC) and fat mass and obesity-associated protein (FTO) as putative therapeutic targets.¹ 

T-ALL is an aggressive hematologic malignancy with limited treatment options upon relapse. Although the transcriptional and genomic landscapes of T-ALL are well described, posttranscriptional mechanisms, particularly RNA modifications, have remained poorly understood. Among these, m⁶A is the most abundant internal RNA modification in eukaryotic mRNA, regulating RNA stability, splicing, and translation in a context-dependent manner. The m⁶A machinery is composed of methyltransferases (“writers” such as METTL3 and METTL14), demethylases (“erasers” like FTO and ALKBH5), and m⁶A-binding proteins (“readers”), which include both the classical YTH domain family proteins (YTHDC1/2, YTHDF1-3) and nonclassical readers such as IGF2BP1-3 and HNRNPs, including HNRNPC, HNRNPG, and HNRNPA2B1.² 

Although m⁶A dysregulation has been established in acute myeloid leukemia (AML), its role in T-ALL has remained underexplored.^3,4 De Kesel et al address this gap using a comprehensive, multiomics approach, integrating RNA sequencing (RNA-seq), m⁶A-enhanced cross linking immunoprecipitation (eCLIP), proteomics, and ribosome profiling across patient-derived models and cell lines. They report widespread remodeling of the m⁶A landscape in T-ALL, including a global reduction in significant m⁶A peaks, with a balanced distribution of hypo- and hypermethylated transcripts. Notably, key oncogenic pathways, particularly MYC targets and cholesterol biosynthesis-related transcripts, were selectively hypermethylated eCLIP suggesting that site-specific, rather than global, m⁶A changes may underlie leukemogenic programs. Correlative analyses across the RNA methylome, transcriptome, and proteome further underscore the biological significance of these m⁶A alterations.

To elucidate the functional role of specific m⁶A readers in T-ALL, the authors mined CRISPR screening data sets and DepMap dependency scores. HNRNPC emerged as a critical dependency. Previously described as an “m⁶A switch” reader that binds U-rich regions structurally modulated by nearby m⁶A marks,⁵ HNRNPC was found to be upregulated in T-ALL. It directly binds methylated transcripts including MYC, HMGCS1, and FDFT1, and its silencing suppressed translation of MYC and metabolic genes, leading to reduced leukemic growth and survival. HNRNPC preferentially bound hypermethylated transcripts, reinforcing its m⁶A-dependent activity. Importantly, not all HNRNPC binding sites overlapped with m⁶A-eCLIP peaks, hinting at possible m⁶A-independent functions in T-ALL.

Strikingly, the role of METTL3 in T-ALL diverged from its function in AML.⁴ Inhibition or knockdown of METTL3 in T-ALL paradoxically increased m⁶A abundance at MYC and cholesterol-related transcripts, alongside elevated MYC expression and cholesterol biosynthesis, despite a global reduction in m⁶A levels. These context-specific effects underscore the transcript-specific, and potentially reader-restricted, consequences of m⁶A regulation and suggest compensatory feedback mechanisms distinct from AML (see figure).

In parallel, the m⁶A demethylase FTO was found to be more highly expressed in T-ALL than in normal thymocytes or AML. Pharmacologic inhibition of FTO using bisantrene⁶ or brequinar⁷ significantly suppressed MYC expression, cholesterol metabolism, and leukemic burden in vitro and in vivo. FTO inhibitors also synergized with dexamethasone and standard chemotherapies, reinforcing their translational potential. These findings align with prior studies in AML but suggest heightened relevance in T-ALL. However, FTO demethylates additional RNA modifications, including m⁶Am and m¹A,⁸ and its genetic silencing yielded more modest effects than pharmacologic inhibition, raising the possibility of broader mechanisms, including inhibition of topoisomerase II and DHODH and previously linked mode of action of these compounds.⁹ 

In conclusion, De Kesel et al provide a foundational framework for understanding the m⁶A epitranscriptome in T-ALL. Their findings identify HNRNPC as a novel oncogenic m⁶A regulator and reinforce the therapeutic potential of targeting RNA methylation programs in T-ALL. The study unveils a complex regulatory axis involving m⁶A, MYC, and metabolic pathways, expanding the landscape of therapeutic targets beyond DNA and chromatin to include RNA-level control of gene expression.

The lineage- and transcript-specific effects of METTL3 underscore the nuanced and context-dependent roles of m⁶A. Future studies should dissect site-specific methylation kinetics; explore feedback loops between MYC signaling, m⁶A dynamics, and metabolism; and develop more selective small-molecule inhibitors or degraders of HNRNPC and FTO. Identifying predictive biomarkers of m⁶A dependence will be key to translating these insights into precision therapies. As with AML, it remains to be determined which T-ALL subtypes are particularly vulnerable to epitranscriptomic perturbation. Overall, this study enriches our understanding of m⁶A-associated vulnerabilities in T-ALL and strengthens the rationale for targeting RNA modifications in hematologic malignancies.

Conflict-of-interest disclosure: X.X. declares no competing financial interests. M.G.K. is a scientific advisory board member of 858 Therapeutics and received laboratory support from AstraZeneca, and consulting and laboratory support from Transition Bio.