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

TL;DR

This study uses single-cell genomics to uncover how T-prolymphocytic leukemia progresses from a slow-growing to an aggressive form.

Contribution

The study identifies MYC-driven metabolic activation and reduced cell interactions as key features in T-PLL progression.

Findings

MYC-target gene signatures are upregulated in active T-PLL, indicating metabolic autonomy.

T-cell receptor signaling genes are downregulated, suggesting escape from regulatory control.

Reduced interactions with non-leukemic cells mark disease progression.

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.

T-prolymphocytic leukemia (T-PLL) is an aggressive T-cell malignancy, but 15–25% of cases are diagnosed at a primarily indolent stage. Here, the authors use single-cell RNA sequencing and whole genome sequencing to study the molecular changes underlying the indolent-to-active evolution of T-PLL, finding patient-specific and common mechanisms of disease progression.

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