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Large Granular Lymphocytic Leukemia: Genomics and Immunome
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Large Granular Lymphocytic Leukemia: Genomics and Immunome

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 37005

Special Issue Editor

Dr. Valeria Visconte

E-Mail Website
Guest Editor
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Interests: myeloid malignancies; bone marrow failure syndromes; RNA splicing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Large granular lymphocytic leukemia is a heterogeneous clonal disease characterized by the chronic proliferation of cytotoxic lymphocytes. A distinct immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) is often found in a subset of patients. The clinical course of the disease encompasses indolent, symptomatic, and aggressive conditions. Integrated genomic analyses have identified alterations in gene pathways (e.g., STAT3, STAT5b) possibly driving cytotoxic clonal proliferation. More importantly, the genetic status of STAT3 and STAT5b has also been correlated with disease severity and immunophenotypic features. Large granular lymphocytic leukemia clones have been found in patients with other bone marrow failure disorders (aplastic anemia, paroxysmal nocturnal hemoglobinuria, and myelodysplastic syndrome), and their presence is sometimes associated with worse survival outcomes. Indeed, STAT3 mutation has been found in some patients with aplastic anemia and MDS with concomitant large granular lymphocytic leukemia clones. The fascinating notion of interconnected pathways and similar pathogenesis explaining this association has been a topic of extensive research. This Special Issue on large granular lymphocytic leukemia will cover the latest discoveries on the genomic landscape of this disease and immunologic aspects of this disorder. Specific emphasis will be given to comprehensive literature reviews highlighting the coexistence of large granular lymphocytic leukemia with other bone marrow failure disorders and the immunologic overview of the disease.

Dr. Valeria Visconte
Guest Editor

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Keywords

  • genetics
  • immune phenotype
  • T-cell clonality

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Published Papers (7 papers)

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Research

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11 pages, 1215 KiB  
Article
Clinicobiological Characteristics and Outcomes of Patients with T-Cell Large Granular Lymphocytic Leukemia and Chronic Lymphoproliferative Disorder of Natural Killer Cells from a Single Institution
by Andrea Rivero, Pablo Mozas, Laura Jiménez, Mónica López-Guerra, Dolors Colomer, Alex Bataller, Juan Correa, Alfredo Rivas-Delgado, Gabriela Bastidas, Tycho Baumann, Alejandra Martínez-Trillos, Julio Delgado, Eva Giné, Elías Campo, Armando López-Guillermo, Neus Villamor, Laura Magnano and Estella Matutes
Cancers 2021, 13(15), 3900; https://doi.org/10.3390/cancers13153900 - 2 Aug 2021
Cited by 14 | Viewed by 3131
Abstract
T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. [...] Read more.
T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of STAT3/STAT5B, treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8+CD57+ group. Remarkably, patients included in the CD4+ group had a higher association with solid tumors (p = 0.037). STAT3 mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying STAT3 mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment (p = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of STAT3. We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of STAT3, and for the first time analyzes survival compared to a matched general Spanish population. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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Review

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18 pages, 1019 KiB  
Review
Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment
by Fauzia Ullah, Mariam Markouli, Mark Orland, Olisaemeka Ogbue, Danai Dima, Najiullah Omar and Moaath K. Mustafa Ali
Cancers 2024, 16(7), 1307; https://doi.org/10.3390/cancers16071307 - 27 Mar 2024
Cited by 7 | Viewed by 6838
Abstract
Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations [...] Read more.
Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations and activation of the JAK-STAT3, Fas/Fas-L and NF-κB signaling pathways. Disease-related deaths are mainly due to recurrent infections linked to severe neutropenia. The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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24 pages, 958 KiB  
Review
Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder
by Mariam Markouli, Fauzia Ullah, Najiullah Omar, Anna Apostolopoulou, Puneet Dhillon, Panagiotis Diamantopoulos, Joshua Dower, Carmelo Gurnari, Sairah Ahmed and Danai Dima
Cancers 2022, 14(23), 5949; https://doi.org/10.3390/cancers14235949 - 1 Dec 2022
Cited by 15 | Viewed by 6642
Abstract
PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a [...] Read more.
PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein–Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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26 pages, 1355 KiB  
Review
Persistent Large Granular Lymphocyte Clonal Expansions: “The Root of Many Evils”—And of Some Goodness
by Carlos Bravo-Pérez, Salvador Carrillo-Tornel, Esmeralda García-Torralba and Andrés Jerez
Cancers 2022, 14(5), 1340; https://doi.org/10.3390/cancers14051340 - 5 Mar 2022
Cited by 10 | Viewed by 5081
Abstract
Large granular lymphocyte leukemia (LGLL) is a chronic disease of either mature phenotype cytotoxic CD3+ T lymphocytes or CD3- NK cells. LGLL diagnosis is hampered by the fact that reactive persistent clonal LGL expansions may fulfill the current criteria for LGLL diagnoses. In [...] Read more.
Large granular lymphocyte leukemia (LGLL) is a chronic disease of either mature phenotype cytotoxic CD3+ T lymphocytes or CD3- NK cells. LGLL diagnosis is hampered by the fact that reactive persistent clonal LGL expansions may fulfill the current criteria for LGLL diagnoses. In addition to the presence of characteristic clinical and hematological signs such as anemia or neutropenia, LGLL/LGL clonal expansions have been associated with an array of conditions/disorders. We review here the presence of these persistent clonal expansions in autoimmune, hematological disorders and solid neoplasms and after hematopoietic stem cell transplantation. These associations are a unique translational research framework to discern whether these persistently expanded LGL clones are causes or consequences of the concomitant clinical settings and, more importantly, when they should be targeted. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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17 pages, 1022 KiB  
Review
The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia
by Valentina Giudice, Matteo D’Addona, Nunzia Montuori and Carmine Selleri
Cancers 2021, 13(18), 4513; https://doi.org/10.3390/cancers13184513 - 8 Sep 2021
Cited by 7 | Viewed by 3081
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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12 pages, 1520 KiB  
Review
Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease
by Misam Zawit, Waled Bahaj, Carmelo Gurnari and Jaroslaw Maciejewski
Cancers 2021, 13(17), 4418; https://doi.org/10.3390/cancers13174418 - 1 Sep 2021
Cited by 18 | Viewed by 6435
Abstract
Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due [...] Read more.
Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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Other

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15 pages, 1519 KiB  
Perspective
LGL Clonal Expansion and Unexplained Cytopenia: Two Clues Don’t Make an Evidence
by Giulia Calabretto, Enrico Attardi, Carmelo Gurnari, Gianpietro Semenzato, Maria Teresa Voso and Renato Zambello
Cancers 2022, 14(21), 5236; https://doi.org/10.3390/cancers14215236 - 25 Oct 2022
Cited by 8 | Viewed by 4383
Abstract
Clonal expansions of large granular lymphocytes (LGL) have been reported in a wide spectrum of conditions, with LGL leukemia (LGLL) being the most extreme. However, the boundaries between LGLL and LGL clones are often subtle, and both conditions can be detected in several [...] Read more.
Clonal expansions of large granular lymphocytes (LGL) have been reported in a wide spectrum of conditions, with LGL leukemia (LGLL) being the most extreme. However, the boundaries between LGLL and LGL clones are often subtle, and both conditions can be detected in several clinical scenarios, particularly in patients with cytopenias. The intricate overlap of LGL clonal expansion with other disease entities characterized by unexplained cytopenias makes their classification challenging. Indeed, precisely assigning whether cytopenias might be related to inadequate hematopoiesis (i.e., LGL as a marginal finding) rather than immune-mediated mechanisms (i.e., LGLL) is far from being an easy task. As LGL clones acquire different pathogenetic roles and relevance according to their diverse clinical settings, their detection in the landscape of bone marrow failures and myeloid neoplasms has recently raised growing clinical interest. In this regard, the current availability of different diagnostic techniques, including next generation sequencing, shed light on the relationship between LGL clones and cytopenias, paving the way towards a better disease classification for precision medicine treatments. Herein, we discuss the clinical relevance of LGL clones in the diagnostic algorithm to be followed in patients presenting with cytopenias, offering a foundation for rational management approaches. Full article
(This article belongs to the Special Issue Large Granular Lymphocytic Leukemia: Genomics and Immunome)
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