Single-cell genomics highlight MYC-upregulation, metabolic activation, and altered cell interactions in T-PLL progression

T-prolymphocytic leukemia (T-PLL) is a rare T-cell malignancy usually associated with rapid tumor progression already at first diagnosis. A small subset of 15-25% of T-PLL patients, however, presents at a primarily indolent disease stage. These patients feature asymptomatic lymphocytosis with stable tumor load over several months to years, before inevitably progressing into active-stage T-PLL. In this study, we employed single-cell RNA sequencing of longitudinally acquired samples to investigate the pathobiologic mechanism underlying this transition from indolent to active T-PLL. We detected consistent deregulations of relevant cancer-associated pathways, centered around a strong upregulation of MYC target gene signatures that highly correlated with an enhanced energy metabolism in active-stage T-PLL cells. Both in silico and ex vivo analyses identified a marked restriction of cell energy metabolism during the indolent disease stage that strongly confined the outgrowth of T-PLL cells. Active T-PLL cells were capable to surpass this metabolic restriction. Analyses of immune-signaling pathways of T-PLL cells as well as the tumor microenvironment further revealed a progressive detachment from immune-related survival signals and escape from the homeostatic control. In summary, we identified both global alterations of gene expression patterns as well as patient-specific lesions that enabled the transformation into active-stage T-PLL. This study provides the first single-cell-resolved genomic analysis of T-PLL, providing valuable and novel insights into the intra-tumor heterogeneity of T-PLL, mechanisms of tumor evolution, as well as its interaction with the tumor microenvironment.