Large granular lymphocyte cells and immune dysregulation diseases – the chicken or the egg?

Langerak, Anton W.; Assmann, Jorn L.J.C.

doi:10.3324/haematol.2017.186338

Cited by 5 publications

(9 citation statements)

References 17 publications

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“…There have been many reported cases of T-LGL leukemia associated with underlying autoimmune disorders, malignancy, bone marrow failure, solid organ transplantation, or use of certain drugs. [2][3][4][5][6]13 In general, it is reported to be an indolent type of leukemia and the…”

Section: Discussionmentioning

confidence: 99%

“…Various T-LGL proliferations have been described in aplastic anemia, pure red cell aplasia, celiac disease, hypoplastic myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, dasatinib therapy, lymphomas, solid organ recipients, and Felty syndrome. [2][3][4][5][6] The pathophysiology of clonal T-LGL proliferations is yet to be explained. The distinction between reactive and malignant entities is not well defined.…”

Section: Introductionmentioning

confidence: 99%

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Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

Savaşan

Al-Qanber

Buck

et al. 2020

Pediatric Blood & Cancer

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Background Proliferation of large granular lymphocytes (LGL) and T‐cell LGL (T‐LGL) in peripheral blood along with demonstration of clonality are the hallmarks of a heterogeneous group of disorders, including T‐LGL leukemia or T‐LGL lymphocytosis. They are often associated with neutropenia and responsive to immunosuppression. The true nature of this entity is not well understood. Some cases are reported as reactive phenomena with very limited experience in pediatric population. Methods Hematology/Oncology Flow Cytometry Laboratory database has been reviewed retrospectively. Patients with identifiable distinct CD5‐dim T‐cell population and positive clonal T‐cell receptor rearrangement were included in the analysis. Clinical and laboratory data were then reviewed. Results Sixteen cases of children and young adults with increased peripheral blood clonal T‐LGL population characterized by dim CD5 expression with wide range of underlying immune dysregulation/stimulation disorders were reviewed. Extended follow up with repeat testing suggested the reactive nature of persistent clonal T‐LGL proliferations in this group. Conclusions Our observations indicate that clonal T‐LGL proliferations in children and young adults are reactive in nature and some can be persistent with an indolent course with unknown consequentiality. Clonal T‐LGL cells could be targeting the most prominent immunogenic stressor(s) involved as a control mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

Savaşan

Al-Qanber

Buck

et al. 2020

Pediatric Blood & Cancer

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“…In addition, IL-15 induces transcription of several anti-apoptotic proteins, such as Bcl-2, while increases proteasome-mediated degradation of pro-apoptotic factors, such as Bid, resulting in increased cell survival [ 35 ]. IL-15 also upregulates MYC , AURKA , and AURKB , responsible for centrosome alterations, and DNMT3B , ultimately leading to hypermethylation of tumor suppressor genes [ 36 , 37 ]. However, pathogenesis of LGL leukemia is not driven only by chronic antigen and proinflammatory cytokine stimulation, but also by constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway and resistance to Fas/Fas-ligand (Fas-L)-mediated apoptosis [ 1 , 2 , 38 ].…”

Section: T-lgl Leukemia Pathogenesismentioning

confidence: 99%

The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia

Giudice

D’Addona

Montuori

et al. 2021

Cancers

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Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of mature T or NK cells frequently associated with autoimmune disorders and other hematological conditions, such as myelodysplastic syndromes. Immunophenotype of LGL cells is similar to that of effector memory CD8+ T cells with T-cell receptor (TCR) clonality defined by molecular and/or flow cytometric analysis. Vβ usage by flow cytometry can identify clonal TCR rearrangements at the protein level, and is fast, sensitive, and almost always available in every Hematology Center. Moreover, Vβ usage can be associated with immunophenotypic characterization of LGL clone in a multiparametric staining, and clonal kinetics can be easily monitored during treatment and follow-up. Finally, Vβ usage by flow cytometry might identify LGL clones silently underlying other hematological conditions, and routine characterization of Vβ skewing might identify recurrent TCR rearrangements that might trigger aberrant immune responses during hematological or autoimmune conditions.

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“…12 However, firm conclusions regarding the precise impact of antigenic drive on T-LGL proliferations could not be drawn and, thus, it remains uncertain if T-LGL cells create an environment for 1 immune-dysregulation disorders to thrive or, instead, arise as a reactive population. 15 Here, we sought to obtain comprehensive insight into the TRB gene repertoire in a series of well-characterized patients with T-LGL lymphoproliferations employing next-generation sequencing (NGS), thus allowing not only to evaluate dominant clonotypes but also to unravel the subclonal architecture. Furthermore, by serial sampling over time and in different disease contexts, we aimed to elucidate if T-LGL lymphoproliferations emerge as reactive populations and how they evolve.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, subcloning of individual TRBV‐TRBD‐TRBJ gene rearrangements followed by Sanger sequencing has also been performed, leading to low‐throughput and low‐resolution datasets 12 . However, firm conclusions regarding the precise impact of antigenic drive on T‐LGL proliferations could not be drawn and, thus, it remains uncertain if T‐LGL cells create an environment for immune‐dysregulation disorders to thrive or, instead, arise as a reactive population 15 …”

Section: Introductionmentioning

confidence: 99%

Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes

et al. 2023

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T cell large granular lymphocyte (T-LGL) lymphoproliferations constitute a disease spectrum ranging from poly/oligo to monoclonal. Boundaries within this spectrum of proliferations are not well established. T-LGL lymphoproliferations co-occur with a wide variety of other diseases ranging from autoimmune disorders, solid tumors, hematological malignancies, post solid organ, and hematopoietic stem cell transplantation, and can therefore arise as a consequence of a wide variety of antigenic triggers. Persistence of a dominant malignant T-LGL clone is established through continuous STAT3 activation. Using next-generation sequencing, we profiled a cohort of 27 well-established patients with T-LGL lymphoproliferations, aiming to identify the subclonal architecture of the T-cell receptor beta (TRB) chain gene repertoire. Moreover, we searched for associations between TRB gene repertoire patterns and clinical manifestations, with the ultimate objective of discriminating between T-LGL lymphoproliferations developing in different clinical contexts and/or displaying distinct clinical presentation. Altogether, our data demonstrates that the TRB gene repertoire of patients with T-LGL lymphoproliferations is context-dependent, displaying distinct clonal architectures in different settings. Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.

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Large granular lymphocyte cells and immune dysregulation diseases – the chicken or the egg?

Cited by 5 publications

References 17 publications

Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia

Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes

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