T-cell large granular lymphocytic (LGL) leukemia consists of CD4&lt;sup&gt;+&lt;/sup&gt;/CD8&lt;sup&gt;dim&lt;/sup&gt; and CD4&lt;sup&gt;-&lt;/sup&gt;/CD8&lt;sup&gt;+&lt;/sup&gt; LGL populations in association with immune thrombocytopenia, autoimmune neutropenia, and monoclonal B-cell lymphocytosis

Kuwahara, Naoya; Kodaka, Takeshi; Zushi, Yuriko; Sasaki, Miho; Goka, Takae; Maruoka, Hayato; Aoyama, Yumi; Tsunemine, Hiroko; Yamane, Taku; Kobayashi, Jun; Kawakami, Toru; Ishida, Fumihiro; Itoh, Tomoo; Takahashi, Takayuki

doi:10.3960/jslrt.19030

Cited by 5 publications

(6 citation statements)

References 20 publications

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“…In CD8+ T-LGLL, STAT3 mutations have been associated with autoimmune manifestations such as rheumatoid arthritis and neutropenia [ 2 , 5 , 8 , 48 , 49 ]. In CD4+ T-LGLL, neutropenia is uncommon, and similarly, in our cohort STAT5B mutated patients had normal ANC levels but increased lymphocyte and LGL counts.…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, CD4+ T-LGLL is usually an indolent disease and unlike in its CD8+ counterpart, these patients rarely have cytopenias or autoimmune symptoms. However, CD4+ T-LGLL has been reported more frequently associated with secondary neoplasms such as monoclonal B-cell lymphocytosis and plasma cell disorders [ 2 , 3 ]. In CD4+ T-LGLL, the leukemic T-LGLs express CD4 (either alone or together with CD8) and the α/β T-cell receptor (TCR) together with a typical mature cytotoxic (Granzyme B+, CD56+, CD57+) and activated/memory T-cell (CD2 bright , CD7 dim , CD11a bright , CD28−, CD62L−) phenotype [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

et al. 2022

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CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E). Multiple STAT5B mutations were present in 22% (5/23) of STAT5B mutated CD4+ T-LGLL cases, either coexisting in one clone or in distinct clones. Patients with STAT5B mutations had increased lymphocyte and LGL counts when compared to STAT5B wild-type patients. TCRβ sequencing showed that, in addition to large LGL expansions, non-leukemic T cell repertoires were more clonal in CD4+ T-LGLL compared to healthy. Interestingly, 25% (15/59) of CD4+ T-LGLL clonotypes were found, albeit in much lower frequencies, in the non-leukemic CD4+ T cell repertoires of the CD4+ T-LGLL patients. Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

et al. 2022

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“…Activating STAT5b mutations have also been found in 55% of CD4+/CD8−/TCRαβ+ T-LGL leukemia patients but are very rare among patients with CD4−/CD8+ T-LGL leukemia or NK-LGL [74]. Similarly, CD3+/CD8+/CD57+ and CD3+/CD4+/CD8 dim /CD57+ phenotypes have been reported in T-LGL with STAT3 mutation, while CD3+/CD4+/CD57+ and CD3+/CD56+ are found in STAT5b mutation [75]. One study demonstrated that the disease course in the CD4+ T-LGL leukemia cohort is indolent, and none of the patients with STAT5b mutations appeared to require therapy during the observation period [74].…”

Section: Molecular Pathway Dysregulationmentioning

confidence: 98%

Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment

Ullah,

Markouli,

Orland

et al. 2024

Cancers

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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.

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“…CD4+lymphocytes and CD8+lymphocytes exert important functions in RA [10,11]. Many autoimmune diseases can be induced by the imbalance of CD4/CD8 ratio [12,13]. Also, the imbalance of CD4+/CD8+ ratio may have a relationship with the pathogenesis of RA [14,15].…”

Section: Introductionmentioning

confidence: 99%

Roles of CD3, CD4 and CD8 in synovial lymphocytes of rheumatoid arthritis

Xiong

Lei

Dong

et al. 2022

pjp

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In this study, the immunohistochemical EnVision method was applied to detect CD3, CD4 and CD8 in synovial tissues of 40 patients with rheumatoid arthritis (RA) and 10 patients with osteoarthritis (OA). In 92.5% (37/40) RA cases, lymphocytes were focally aggregated, and even germinal centers appeared, forming lymphoid follicle-like structures. The expression of CD3, CD4, and CD8 were high in synovial tissue of RA group, but low in OA group. The number of CD3, CD4+, and CD8+ lymphocytes in OA group were significantly lower than that in RA group (p < 0.05); CD4+lymphocytes in RA accounted for the majority, and mostly were focally distributed. The number of CD8+lymphocytes in the synovial tissue were small, and were mostly scattered. The number of CD4+lymphocytes were significantly higher than CD8+lymphocytes (p<0.05). Compared with the OA group, the number of CD4+T and CD8+T lymphocytes in RA group were higher, and the ratio of CD4/CD8 was higher in RA group (p < 0.05). In conclusion, the CD3, CD4 and CD8 with high level may promote the occurrence and development of RA. The ratio of CD4+/CD8+ may be used as a reference index for the diagnosis and prognosis of RA.

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T-cell large granular lymphocytic (LGL) leukemia consists of CD4<sup>+</sup>/CD8<sup>dim</sup> and CD4<sup>-</sup>/CD8<sup>+</sup> LGL populations in association with immune thrombocytopenia, autoimmune neutropenia, and monoclonal B-cell lymphocytosis

Cited by 5 publications

References 20 publications

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment

Roles of CD3, CD4 and CD8 in synovial lymphocytes of rheumatoid arthritis

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