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<p>T-prolymphocytic leukemia (T-PLL) typically presents with rapidly progressing tumor burden. However, 15–25% of cases are diagnosed at an indolent stage with asymptomatic and stable low-level blood lymphocytosis over up to 2-3 years before advancing to active-stage disease. To define the molecular changes underlying this transition, we perform single-cell RNA sequencing of 28 treatment-naïve samples including 11 longitudinally acquired indolent/active pairs, paralleled by longitudinal whole genome sequencing. This reveals both patient-specific lesions and common global alterations of gene expression. Strong upregulations of MYC-target gene signatures in active T-PLL samples associated with enhanced energy metabolism implicate acquired autonomy from energetic restrictions. Recurrent downregulation of genes of the T-cell-receptor signaling cascade and reduced interactions of the T-PLL cell with non-leukemic cell types further indicate progressive independence from regulatory survival signals and escape from micromilieu-mediated control. This single-cell and disease-stage resolved genomic analysis of T-PLL provides insights into shared mechanisms of tumor evolution, which have to prove their amenability as targetable lesions.</p>

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Single-cell genomics highlight MYC-associated metabolic activation and altered cell interactions in T-prolymphocytic leukemia progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Linus Wahnschaffe,
  • Dennis Jungherz,
  • Tony A. Müller,
  • Tea Pemovska,
  • Alexander Pichler,
  • Stéphanie Poulain,
  • Edith Julia,
  • Sanna Timonen,
  • Martin Böttcher,
  • Qu Jiang,
  • David Beverungen,
  • Julia Bischoff,
  • Marek Franitza,
  • Theodoros Georgomanolis,
  • Kerstin Becker,
  • Michael Hallek,
  • Dimitrios Mougiakakos,
  • Thorsten Zenz,
  • Satu Mustjoki,
  • Emmanuel Bachy,
  • Charles Herbaux,
  • Alexandra Schrader,
  • Natali Pflug,
  • Philipp B. Staber,
  • Till Braun,
  • Marco Herling

摘要

T-prolymphocytic leukemia (T-PLL) typically presents with rapidly progressing tumor burden. However, 15–25% of cases are diagnosed at an indolent stage with asymptomatic and stable low-level blood lymphocytosis over up to 2-3 years before advancing to active-stage disease. To define the molecular changes underlying this transition, we perform single-cell RNA sequencing of 28 treatment-naïve samples including 11 longitudinally acquired indolent/active pairs, paralleled by longitudinal whole genome sequencing. This reveals both patient-specific lesions and common global alterations of gene expression. Strong upregulations of MYC-target gene signatures in active T-PLL samples associated with enhanced energy metabolism implicate acquired autonomy from energetic restrictions. Recurrent downregulation of genes of the T-cell-receptor signaling cascade and reduced interactions of the T-PLL cell with non-leukemic cell types further indicate progressive independence from regulatory survival signals and escape from micromilieu-mediated control. This single-cell and disease-stage resolved genomic analysis of T-PLL provides insights into shared mechanisms of tumor evolution, which have to prove their amenability as targetable lesions.