Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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.

SUBMITTER: Braun T

PROVIDER: S-EPMC8639578 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

T-cell Prolymphocytic Leukemia, Cerebriform Variant.

Project description:T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive lymphoproliferative disorder. We present a 70-year-old man with complaints of fatigue, low urinary output, and peripheral edema for one month. Objectively, he presented diminished respiratory sounds bilaterally and peripheral edema. Analytical study revealed mild anemia and mild lymphomonocytosis, acute kidney injury, and urinalysis with proteins, leukocytes, erythrocytes, and cylinders. Chest radiography was consistent with pleural effusion. Subsequent study showed new onset of thrombocytopenia with a progressive increase of lymphocytosis, in association with inguinal adenopathies and splenomegaly. Immunophenotypic study of peripheral blood and lymph node biopsy were compatible with the diagnosis of T-PLL. Negative serology for human T-cell lymphotropic virus type 1 (HTLV-1) excluded adult T-cell leukemia. Progressive changes in the peripheral blood smear were seen, finally showing the presence of lymphocytes with a cerebriform nucleus, revealing this variant. There was a rapid catastrophic progression, spontaneous tumor lysis syndrome, and death.

| S-EPMC7956018 | biostudies-literature

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

Project description:T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 (TCL1) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.

| S-EPMC10419310 | biostudies-literature

T-cell prolymphocytic leukemia and tuberculosis: a puzzling association.

Project description:T-cell prolymphocytic leukemia can result in severe immune T-cell deficiency. Clinicians should be aware of this complication in this rare lymphoid malignancy, and opportunistic infections should be ruled out before the use of usual immunosuppressive procedures such as alemtuzumab and hematopoietic stem cell transplantation.

| S-EPMC5582236 | biostudies-literature

SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia.

Project description:T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1. SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, and HERC2) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.

| S-EPMC5802577 | biostudies-literature

Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia.

Project description:T cell prolymphocytic leukemia (T-PLL) is a rare, mature T cell neoplasm with distinct features and an aggressive clinical course. Early relapse and short overall survival are commonplace. Use of the monoclonal anti-CD52 antibody alemtuzumab has improved the rate of complete remission and duration of response to more than 50% and between 6 and 12 months, respectively. Despite this advance, without an allogeneic transplant, resistant relapse is inevitable. We report seven complete and one partial remission in eight patients receiving alemtuzumab and cladribine with or without a histone deacetylase inhibitor. These data show that administration of epigenetic agents can overcome alemtuzumab resistance. We also report epigenetically induced expression of the surface receptor protein CD30 in T-PLL. Subsequent treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin overcame organ-specific (skin) resistance to alemtuzumab. Our findings demonstrate activity of combination epigenetic and immunotherapy in the incurable illness T-PLL, particularly in the setting of previous alemtuzumab therapy.

| S-EPMC4807901 | biostudies-literature

B-cell prolymphocytic leukemia

Project description:We evaluated 13 B-PLL patient, 7 of whom were t(11;14)-positive (B-PLL+), and compared them with MCL and CLL patients.

2014-05-29 | E-MTAB-1991 | biostudies-arrayexpress

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.

Project description:The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.

| S-EPMC4148768 | biostudies-literature

Delayed Diagnosis of T-Cell Prolymphocytic Leukemia: Approach to Chronic Lymphocytosis.

Project description:We present a case of lymphocytosis assumed and managed initially as a chronic lymphocytic leukemia. Shortly after initial visit, the patient's condition deteriorated rapidly with hepatosplenomegaly, pleural effusion, ascites, and skin lesions. Flow cytometry (FC) showed the presence of clonal T-cell population, reported as T-cell lymphoma. Due to rapid clinical deterioration, urgent therapy with cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone was initiated, but with minimal response. This prompted further diagnostic testing and demonstrated tumor cells positivity for CD3, CD30, and TCL1 markers. The diagnosis was changed to T-cell prolymphocytic leukemia. The patient responded well to alemtuzumab (anti-CD52 monoclonal antibody) and reached complete remission. FC is an essential modality for assessing and screening circulating lymphocytes when a lymphoproliferative disorder (LPD) is suspected. There are several LPDs that present with different degrees of clonal lymphocytosis. Reactive lymphocytosis should be appropriately investigated. Indolent LPDs can be surveyed by the internist or family physician, while more aggressive LPDs typically require management by hematologists.

| S-EPMC10601740 | biostudies-literature

CCR7 as a novel therapeutic target in t-cell PROLYMPHOCYTIC leukemia.

Project description:T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.Supplementary informationSupplementary information accompanies this paper at 10.1186/s40364-020-00234-z.

| S-EPMC7585232 | biostudies-literature

Anti-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia.

Project description:T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy characterized by chemotherapy resistance and a median survival of less than 2 years. Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. Importantly, all T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations, while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray-based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL.

| S-EPMC7570784 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data