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<p><i>TAL1</i> 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 <i>TAL1</i> transcript quantification, though this technique may be subject to interference by <i>TAL1</i> transcripts deriving from residual haematological cells that physiologically express high levels of the gene. We hypothesised <i>TAL1</i> DNA methylation could provide a more reliable biomarker than <i>TAL1</i> transcript quantification alone. We extensively studied <i>TAL1</i> dysregulation in a large adult and paediatric T-ALL cohort (<i>n</i> = 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 <i>TAL1</i> hypomethylated (methylation ratio &lt;0.4), biallelic TAL1 + T-ALL were enriched in expression of other driver oncogenes (<i>TLX1, TLX3, HOXA</i>), and had heterogeneous transcriptomes and <i>TAL1</i> methylation levels. In PDX analysis, monoallelic <i>TAL1</i> expression was stable, contrary to biallelic expression which mostly derived from residual non-malignant haematopoietic cells. Importantly, we report 5 novel <i>TAL1</i> dysregulation mechanisms using long-read nanopore and OGM analysis, and show that <i>TAL1</i> hypomethylation identifies TAL1 dysregulation, and is associated with worse prognosis.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月8日

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  • Charlotte Smith,
  • Guillaume Charbonnier,
  • Mathieu Simonin,
  • Estelle Balducci,
  • Thomas Steimle,
  • Guillaume P. Andrieu,
  • Agata Cieslak,
  • Marianne Courgeon,
  • Marc LeLorc’h,
  • Anand Mayakonda,
  • Christoph Plass,
  • Aurélie Le Nezet,
  • Mehdi Latiri,
  • Norbert Ifrah,
  • Hervé Dombret,
  • Françoise Huguet,
  • André Baruchel,
  • Elizabeth Macintyre,
  • Arnaud Petit,
  • Nicolas Boissel,
  • Vahid Asnafi,
  • Aurore Touzart

摘要

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.