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ACUTE LYMPHOBLASTIC LEUKEMIA

Towards methylation-based redefinition of TAL1 positive T-cell acute lymphoblastic leukaemia (T-ALL)

Leukemia volume 39, pages 2344–2354 (2025)Cite this article

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Abstract

TAL1 is one of the most frequently dysregulated oncogenes in T-cell Acute Lymphoblastic Leukaemia (T-ALL). However, the precise frequency and prognostic impact associated with its dysregulation remains unclear and is confounded by TAL1’s diverse dysregulation mechanisms. TAL1 dysregulation is detected by TAL1 transcript quantification, though this technique may be subject to interference by TAL1 transcripts deriving from residual haematological cells that physiologically express high levels of the gene. We hypothesised TAL1 DNA methylation could provide a more reliable biomarker than TAL1 transcript quantification alone. We extensively studied TAL1 dysregulation in a large adult and paediatric T-ALL cohort (n = 401) and designed a TAL1 specific MS-MLPA assay to determine methylation levels. Whereas monoallelic TAL1 + T-ALL had homogeneous gene expression profiles, never expressed other driver oncogenes and were TAL1 hypomethylated (methylation ratio <0.4), biallelic TAL1 + T-ALL were enriched in expression of other driver oncogenes (TLX1, TLX3, HOXA), and had heterogeneous transcriptomes and TAL1 methylation levels. In PDX analysis, monoallelic TAL1 expression was stable, contrary to biallelic expression which mostly derived from residual non-malignant haematopoietic cells. Importantly, we report 5 novel TAL1 dysregulation mechanisms using long-read nanopore and OGM analysis, and show that TAL1 hypomethylation identifies TAL1 dysregulation, and is associated with worse prognosis.

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Fig. 1: TAL1 + T-ALL are heterogeneous and the majority have unresolved TAL1 dysregulation mechanisms.
Fig. 2: Detection of structural variants affecting TAL1 using optical genome mapping (OGM).
Fig. 3: Monoallelic TAL1+ T-ALL have low TAL1 methylation.
Fig. 4: Monoallelic and Biallelic TAL1 + T-ALL have distinct gene expression profiles.
Fig. 5: TAL1 hypomethylation is a biomarker of monoallelic TAL1 dysregulation.
Fig. 6: TAL1 hypomethylation identifies a subgroup of T-ALL associated with poor prognosis.

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Data availability

For EPIC data, all microarray raw IDAT files have been deposited to Gene Expression Omnibus (GEO) under the accession number GSE147667 as detailed in [29].

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Acknowledgements

We would like to thank all participants in the GRAALL-2003 and GRAALL-2005 study groups, the SFCE and the investigators of the 16 SFCE centres involved in collection and provision of data and patient samples, and V. Lheritier for collection of clinical data.

Funding

The GRAALL was supported by grants P0200701 and P030425/AOM03081 from the Programme Hospitalier de Recherche Clinique, Ministère de l’Emploi et de la Solidarité, France and the Swiss Federal Government in Switzerland. Samples were collected and processed by the AP-HP “Direction de Recherche Clinique” Tumour Bank at Necker-Enfants Malades. We would also like to thank La Fondation pour la Recherche Médicale for their support through the grant FDT202012010638 which was awarded to CS and “La Ligue Contre le Cancer” for supporting MS.

Author information

Authors and Affiliations

  1. Université Paris Cité, Institut Necker Enfants-Malades INEM, Institut National de la Santé et de la Recherche Médicale (Inserm) U1151, Paris, France

    Charlotte Smith, Guillaume Charbonnier, Mathieu Simonin, Estelle Balducci, Thomas Steimle, Guillaume P. Andrieu, Agata Cieslak, Marianne Courgeon, Aurélie Le Nezet, Mehdi Latiri, Elizabeth Macintyre, Vahid Asnafi & Aurore Touzart

  2. Laboratory of Onco-hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France

    Charlotte Smith, Guillaume Charbonnier, Estelle Balducci, Thomas Steimle, Guillaume P. Andrieu, Agata Cieslak, Marianne Courgeon, Aurélie Le Nezet, Mehdi Latiri, Elizabeth Macintyre, Vahid Asnafi & Aurore Touzart

  3. Service d’Hématologie et d’Oncologie pédiatrique, AP-HP, Hôpital Armand Trousseau, Sorbonne Université, Paris, France

    Mathieu Simonin & Arnaud Petit

  4. Service de Médecine Génomique des Maladies Rares, Groupe Hospitalier Necker-Enfants Malades, Paris, France

    Marc LeLorc’h

  5. Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Anand Mayakonda & Christoph Plass

  6. German Cancer Research Consortium (DKTK), Heidelberg, Germany

    Christoph Plass

  7. UFR Santé, Université Angers, PRES LUNAM, Centre Hospitalier-Universitaire (CHU) d’Angers, Service des Maladies du Sang et INSERM U892, Angers, France

    Norbert Ifrah

  8. Université Paris Cité, Institut Universitaire d’Hématologie, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Paris, France

    Hervé Dombret & Nicolas Boissel

  9. Service d’Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse, Oncopole, France

    Françoise Huguet

  10. Department of Pediatric Hematology and Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Robert Debré Hospital, Université Paris Cité, Paris, France

    André Baruchel

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  1. Charlotte Smith
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  2. Guillaume Charbonnier
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Contributions

CS designed and carried out experiments, visualised data, and wrote the original manuscript, GC carried out RNA-seq bioinformatic analysis and visualised the data. MS analysed and visualised clinical data. EB analysed and visualised OGM data. TS processed, analysed, and visualised WGS data. GA analysed and visualised NGS data. MLL, ML, and ALN carried out experiments. VA and AT offered expertise and supervised the research. CS, GC, MS, EB, TS, GA, AC, MC, MLL, AM, CP, ALN, ML, NI, HD, FH, AB, EM, AP, NB, VA, and AT all critically reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Vahid Asnafi or Aurore Touzart.

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The authors declare no competing interests.

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Both adult and paediatric trials included in this study were conducted in accordance with the Declaration of Helsinki and approved by local and multicentre research ethical committees. Consent was obtained from all patients at trial entry. Animal experimentation was evaluated and approved by the Institute’s ethics committee and the Ministère de l’enseignement supérieur de la recherche et de l’innovation.

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Smith, C., Charbonnier, G., Simonin, M. et al. Towards methylation-based redefinition of TAL1 positive T-cell acute lymphoblastic leukaemia (T-ALL). Leukemia 39, 2344–2354 (2025). https://doi.org/10.1038/s41375-025-02714-3

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