Abstract
T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia. It is a typically aggressively growing and chemotherapy-resistant malignancy with a poor prognosis. T-PLL cells resemble activated, post-thymic T-lymphocytes with memory-type effector functions. Constitutive transcriptional activation of genes of the T-cell leukemia 1 (TCL1) family based on genomic inversions/translocations is recognized as a key event in T-PLL’s pathogenesis. TCL1’s multiple effector pathways include the enhancement of T-cell receptor (TCR) signals. New molecular dependencies around responses to DNA damage, including repair and apoptosis regulation, as well as alterations of cytokine and non-TCR activation signaling were identified as perturbed hallmark pathways within the past years. We currently witness these vulnerabilities to be interrogated in first pre-clinical concepts and initial clinical testing in relapsed/refractory T-PLL patients. We summarize here the current knowledge on the molecular understanding of T-PLL’s pathobiology and critically assess the true translational progress around this to help appraisal by caregivers and patients. Overall, the contemporary concepts on T-PLL’s pathobiology are condensed in a comprehensive mechanistic disease model and promising interventional strategies derived from it are highlighted.
Highlights
T-cell prolymphocytic leukemia (T-PLL) is an aggressive peripheral T-cell malignancy [1] and represents the most common mature T-cell leukemia in Western countries [2]
In accordance with the finding that virtually all T-PLL express the surface T-cell receptor (TCR) complex [18], the other allele of the analyzed T-PLL cases showed legitimate TRA rearrangements, leading to the expression of a functional TCR [17]. These findings suggest, that the aberrant TRA-TCL1A/MTCP1 rearrangements occur during the opening of the TRA locus at the CD4/CD8 dp thymocyte stage in a RAG1/2 dependent manner [17], followed by legitimate recombination of the locus on the other allele
Enhanced TCR signaling is further established in T-PLL cells by impaired control mechanisms [model (iii)], e.g. by downregulation of negative coregulators such as SLAMFs or checkpoint molecules such as CTLA4 [10]
Summary
T-cell prolymphocytic leukemia (T-PLL) is an aggressive peripheral T-cell malignancy [1] and represents the most common mature T-cell leukemia in Western countries (incidence ≈ 2.0/million/ year) [2]. Molecular hallmarks around perturbed responses to DNA damage, including repair and apoptosis, as well as alterations of cytokine signaling and epigenetic deregulations, were identified as exploitable dependencies. Besides the highly prevalent structural lesions involving the oncogenes TCL1A, AGO2, and MYC, as well as in the tumor suppressor ATM, various single-nucleotide variants (SNVs) were linked to the molecular pathogenesis of T-PLL cells [10, 26, 35, 36].
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