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.