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

Wahnschaffe L, Jungherz D, Müller TA, Pemovska T, Pichler A, Poulain S, Julia E, Timonen S, Böttcher M, Jiang Q, Beverungen D, Bischoff J, Franitza M, Georgomanolis T, Becker K, Hallek M, Mougiakakos D, Zenz T, Mustjoki S, Bachy E, Herbaux C, Schrader A, Pflug N, Staber PB, Braun T, Herling M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 17

Article Number: 2319

Journal Issue: 1

DOI: 10.1038/s41467-026-70185-w

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.

Involved external institutions

Universitätsklinikum Köln DE Germany (DE) Medizinische Universität Wien AT Austria (AT) LILLE 1 University - Science and Technology FR France (FR) Centre International de Recherche en Infectiologie (CIRI) FR France (FR) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) FI Finland (FI) Universitätsklinikum Magdeburg A.ö.R. DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universität zu Köln DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH) Centre Hospitalier Universitaire de Montpellier (CHU/CHRU MTP) FR France (FR)

How to cite

APA:

Wahnschaffe, L., Jungherz, D., Müller, T.A., Pemovska, T., Pichler, A., Poulain, S.,... Herling, M. (2026). Single-cell genomics highlight MYC-associated metabolic activation and altered cell interactions in T-prolymphocytic leukemia progression. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-70185-w

MLA:

Wahnschaffe, Linus, et al. "Single-cell genomics highlight MYC-associated metabolic activation and altered cell interactions in T-prolymphocytic leukemia progression." Nature Communications 17.1 (2026).

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