Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias.
Ontology highlight
ABSTRACT:
SUBMITTER: Oshimi K
PROVIDER: S-EPMC5548667 | biostudies-other | 2017
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.
| S-EPMC8534439 | biostudies-literature
Project description:Large granular lymphocytic leukemia (LGLL) represents a clonal/oligoclonal lymphoproliferation of cytotoxic T and natural killer cells often associated with STAT3 mutations. When symptomatic, due to mostly anemia and neutropenia, therapy choices are often empirically-based, because only few clinical trials and systematic studies have been performed. Incorporating new molecular and flow cytometry parameters, we identified 204 patients fulfilling uniform criteria for LGLL diagnoses and analyzed clinical course with median follow-up of 36 months, including responses to treatments. While selection of initial treatment was dictated by clinical features, the initial responses, as well as overall responses to methotrexate (MTX), cyclosporine (CsA), and cyclophosphamide (CTX), were similar at 40-50% across drugs. Sequential use of these drugs resulted in responses in most cases: only 10-20% required salvage therapies such as ATG, Campath, tofacitinib, splenectomy or abatacept. MTX yielded the most durable responses. STAT3-mutated patients required therapy more frequently and had better overall survival.
| S-EPMC8694069 | biostudies-literature
Project description:Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.
| S-EPMC2786937 | biostudies-literature
Project description:The bone marrow microenvironment in Large Granular Lymphocyte Leukemia (LGLL) patients has been unexplored for it’s role in the development of cytopenias, which lead to complications resulting in the most prominent causes of morbidity and mortality. We used microarrays on primary mesenchymal stem cell (MSC) cultures isolated from bone marrow aspirates from LGLL patients to identify genetic programs that may lead to the observed profibrotic and extrinsically senescent phenotype.
2013-04-20 | GSE37470 | GEO
Project description:The bone marrow microenvironment in Large Granular Lymphocyte Leukemia (LGLL) patients has been unexplored for it’s role in the development of cytopenias, which lead to complications resulting in the most prominent causes of morbidity and mortality. We used microarrays on primary mesenchymal stem cell (MSC) cultures isolated from bone marrow aspirates from LGLL patients to identify genetic programs that may lead to the observed profibrotic and extrinsically senescent phenotype. Isolated primary MSC cultures were maintained under reduced oxygen conditions (2%). All cultures displayed trilineage pluripotency (adipogenesis, osteogenesis, and chondrogenesis). For comparison, normal MSC cultures in early passage (p2-3; same number of population doublings as the LGLL MSCs) and later passage (p7-9; same time spent in culture as the LGLL MSCs) are included.
2013-04-20 | E-GEOD-37470 | biostudies-arrayexpress
Project description:Eastern Clinical Oncology Group trial number 5998 determined the efficacy of the immunosupressives methotrexate (step 1) and cylophosphamide (step 2) in the treatment of Large Granular Lymphocyte leukemia. Expression data from pre-treatment samples were evaluated for a priori ability to predict treatment response to Step 1 and for correlation with STAT3 mutation types predictive of response. Method: patient PBMCs from Ficoll, normal patient PBMCS enriched for CD3+/CD8+ or CD3+/CD8+/CD45RA+/CCR7- were extracted in Trizol. Conclusion: A gene expression profile was associated with response to treatment with evidence of particular STAT3 mutations driving this expression profile and response.
2014-12-29 | GSE42664 | GEO
Project description:TCRγδ+ T-LGL leukemia is a rare form of chronic mature T cell disorders in elderly, which is generally characterized by a persistently enlarged CD3+CD57+TCRγδ+ large granular lymphocyte population in the peripheral blood with a monoclonal phenotype. Clinically, the disease is heterogeneous, most patients being largely asymptomatic, although neutropenia, fatigue and B symptoms and underlying diseases such as autoimmune diseases or malignancies are also often observed. The etiology of TCRγδ+ T-LGL proliferations is largely unknown. Here, we aimed to investigate underlying molecular mechanisms of these rare proliferations by performing gene expression profiling of TCRγδ+ T-LGL versus normal TCRγδ+ T cell subsets. From our initial microarray dataset we observed that TCRγδ+ T-LGL leukemia forms a separate group when compared with different healthy control TCRγδ+ T cell subsets, correlating best with the healthy TemRA subset. The lowest correlation was seen with the naive subset. Based on specific comparison between healthy control cells and TCRγδ+ T-LGL leukemia cells we observed up-regulation of survival, proliferation and hematopoietic system related genes, with a remarkable down-regulation of apoptotic pathway genes. RQ-PCR validation of important genes representative for the dataset, including apoptosis (XIAP, CASP1, BCLAF1 and CFLAR), proliferation/development (ID3) and inflammation (CD28, CCR7, CX3CR1 and IFNG) processes largely confirmed the dysregulation in proliferation and apoptosis. Based on these expression data we conclude that TCRγδ+ T-LGL leukemia is likely the result of an underlying aberrant molecular mechanisms leading to increased proliferation and reduced apoptosis.
| S-EPMC5391076 | biostudies-literature
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described.
2012-08-03 | GSE39838 | GEO
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described. Mononuclear cells were separated from peripheral blood by density gradient sedimentation (Mediatech, Herndon, VA, USA). LGL cells were separated by flow cytometric sorting using anti-VB and CD8 mAb as described previously. Healthy, donor-derived CD8+CD57+ cells were isolated by flow cytometric sorting using CD3, CD8, and CD57 mAb. Total RNA was extracted from cells using Trizol (Invitrogen, Carlsbad, CA, USA) Phase-Lock gel tubes (Eppendorf, Hamburg, Germany), cleaned RNAeasy columns (Qiagen, Valencia CA, USA), and dissolved diethylpyrocarbonate water. Total cRNA was prepared using the in vitro-transcribed (Affymetrix, Santa Clara, CA, USA) and hybridized to U133 arrays, according to the manufacturer's instructions (Affymetrix). All microarrays were examined for surface defects, grid placement, background intensity, housekeeping gene expression, and a 3:5 ratio of probe from genes of varying length. Expression analysis was conducted using standard Affymetrix analysis software algorithms (Microarray Suite 5.0). Comparative analysis between expression profiles was carried out on GeneSpring' software, Version 7.1 (Agilent, Clara, CA, USA). Scanned images of Affymetrix chips were converted spreadsheet numbers using Affymetrix proprietary GeneChip Operating software (GCOS).
2012-08-02 | E-GEOD-39838 | biostudies-arrayexpress
Project description:Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.
| S-EPMC5792275 | biostudies-other