Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

Abstract

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Reconstruction of rearranged T‐cell receptor loci by whole genome and transcriptome sequencing gives insights into the initial steps of T‐cell prolymphocytic leukemia

“…TRAV41 and TRDV2. Thus, the occurrence of the hallmark event coincides with and prevents physiological down-regulation of TCL1A (Figure 1D) 7. Finally, we investigated the expression of the TRD locus on the basis of RNAseq data.…”

“…Thus, the occurrence of the hallmark event coincides with and prevents physiological down-regulation of TCL1A ( Figure 1D). 7 The illegitimate TRA/TRD rearrangements in T-PLL prevent expression of a functional TCR alpha or delta in tumor cells from the affected allele. Taking into consideration that T-PLL cells nevertheless not only express a functional T-cell receptor but also seem to rely on that, [15][16][17] we investigated the second allele of chromosome 14 in which the TRA/TRD locus remains unaffected by the cancer-related aberration.…”

“…Nevertheless, it needs to be emphasized that our study does not claim that these are the "initial" steps of T-PLL pathogenesis, as this would require chronologic alignments of illegitimate TRA rearrangements with ATM mutations, since the latter occur in the vast majority of T-PLL. 7,22 The increased incidence of T-PLL in patients with germline mutations in ATM 23 and the function of the ATM protein in repair of RAG-mediated DNA breaks might suggest that ATM dysfunction, whether encoded by germline or somatic genetic changes or due to stochastic alterations in expression, might contribute to the occurrence of illegitimate TRA rearrangements in T-PLL. 17,24 This would suggest a model in which ATM alterations take place before TRA rearrangements in T-PLL, which needs to be tested in future studies.…”

“…during T-cell development is observed up to CD4+ immature single positive (CD4 ISP) stage, whereas it is silenced in later stages of T-cell development4,7 (Figure 1D).To gain further insights into the T-cell maturation stage at which the TCL1A/MTCP1 inversions/translocations occur we investigated the junctional sequences of the illegitimate rearrangements leading to the oncogenic fusions at the TRA/TRD locus in 14q11. We observed that all 17 T-PLL cases (including SUP-T11) have a breakpoint at a recombination signal sequence (RSS) of the J region of TRA (JA) and juxtapose the TRA enhancer (Ea) in cis to the TCL1A/MTCP1 gene(s).…”

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…The functional relevance of the HR pathway for tumor suppression is underscored by the observation that patients with heterozygous germline variants in a multitude of HR-related genes, including BRCA1 , BRCA2 and RAD51C , display a substantially elevated cancer risk [35,36,37,38,39,40]. Moreover, mutations in BRCA1 , BRCA2 , ATM , CHEK2 , RAD50 , RAD51C and others have been repeatedly identified in numerous cancer entities, including, but not limited to, PDAC, non-small cell lung cancer, ovarian cancer, as well as chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia and mantle cell lymphoma [17,41,42,43,44,45,46]. …”