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

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.

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Journal
Nature Communications
Published
2026-03-09
DOI
https://doi.org/10.1038/s41467-026-70185-w
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Qu Jiang, Martin Böttcher, Theodoros Georgomanolis, Stéphanie Poulain et al.
Nature Communications
Chronic Lymphocytic Leukemia Research
article

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

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

Abstract

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.

Nature CommunicationsVol. 17(1)
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), University of Helsinki (FI), Inserm (FR), University of Cologne (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University of Zurich (CH), Université de Lille (FR), Helsinki University Hospital (FI), Vienna General Hospital (AT), Universitätsklinikum Erlangen (DE), Düsseldorf University Hospital (DE), Lille’s Cardiology Hospital (FR), Comprehensive Cancer Center Vienna (AT), Centre Hospitalier Universitaire de Montpellier (FR), Integrated Oncology (United States) (US), University Hospital of Zurich (CH), Hospices Civils de Lyon (FR), University Hospital Münster (DE), University Hospital Leipzig (DE), Institute for Molecular Medicine Finland (FI), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Magdeburg (DE), Comprehensive Cancer Center Erlangen (DE), University Hospital Cologne (DE), Centre International de Recherche en Infectiologie (FR), Heinrich Heine University Düsseldorf (DE), Medical University of Vienna (AT), Leipzig University (DE), Otto-von-Guericke-Universität Magdeburg (DE)
Helsingin Yliopisto, Université de Lille, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Austrian Science Fund, Universität Wien, Centre National de la Recherche Scientifique, José Carreras Leukämie-Stiftung, Medizinische Universität Wien, Deutsche Krebshilfe, Sächsisches Staatsministerium für Wissenschaft und Kunst, Institut National Du Cancer, Universität Zürich, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Universität zu Köln, Syöpäsäätiö, Universitätsklinikum Köln, Helsinki Institute of Life Science, Helsingin Yliopisto
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