Journal
FRONTIERS IN ONCOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.775363
Keywords
T-PLL; clonal evolution; pathogenesis; TCL1A; ATM
Categories
Funding
- DFG Research Unit FOR1961 [HE3553/4-2]
- Koln Fortune Program
- Fritz Thyssen Foundation [10.15.2.034MN]
- EU Transcan-2 consortium `ERANET-PLL' [01KT1906A/B]
- ERAPerMed consortium 'JAKSTAT-TARGET' [ERAPERMED2018-066]
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T-cell prolymphocytic leukemia (T-PLL) is a common and aggressive mature T-cell leukemia with resistance to chemotherapy. The constitutive transcriptional activation of the TCL1 gene family is a key event in its pathogenesis. New molecular dependencies and altered signaling pathways have been identified as hallmark features in recent years, providing insights for potential therapeutic interventions in T-PLL patients, both pre-clinically and clinically.
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.
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