Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact

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.

Computational gene expression analysis reveals distinct molecular subgroups of T-cell prolymphocytic leukemia

“…Additional studies are required to predict such genes. A promising strategy would be the analysis of genome-wide T-PLL-specific gene regulatory networks with the help of network flow algorithms to identify subgroup-specific driver candidates [5]. The value of such approaches has already been demonstrated for other types of cancer [67][68][69].…”

“…T-cell prolymphocytic leukemia (T-PLL) is a rare but highly malignant mature T-cell leukemia with aggressive clinical course and high mortality rates [1][2][3][4][5]. T-PLL was first described by [6] almost 50 years ago.…”

“…Increasing evidences suggest that chromosomal aberrations are a main driver of T-PLL development. Especially the TCL1 gene family, the ATM gene, and DNA copy number alterations affecting chromosome 8 have been identified as pathogenic or prognostic factors of T-PLL [4,5]. In most cases, complex T-PLL karyotypes show an overexpression of the protooncogene TCL1A at chromosome 14q32.1 due to an inversion (inv (14)(q11;q32)) or a translocation (t(14;14)(q11;q32)) [4,5,17].…”

“…Especially the TCL1 gene family, the ATM gene, and DNA copy number alterations affecting chromosome 8 have been identified as pathogenic or prognostic factors of T-PLL [4,5]. In most cases, complex T-PLL karyotypes show an overexpression of the protooncogene TCL1A at chromosome 14q32.1 due to an inversion (inv (14)(q11;q32)) or a translocation (t(14;14)(q11;q32)) [4,5,17]. This activation of TCL1A is frequently observed in combination with the inactivation of the tumor suppressor ATM at chromosome 11q22.3 by deletions and/or missense mutations [17][18][19].…”

T-Cell Prolymphocytic Leukemia: Diagnosis, Pathogenesis, and Treatment

“…Improved understanding of T-PLL pathogenesis has exposed novel vulnerabilities that are currently being explored pre-clinically and in early-phase clinical trials (Table 5), some of which have been recently reviewed [72,73], and have been identified in an unbiased ex vivo drug screen [47]. These novel therapeutic strategies (represented in Figure 4), informed by an improved understanding of T-PLL pathogenesis, suggest that we may be on the dawn of a new era in T-PLL management.…”