T cell large granular lymphocyte leukemia and chronic NK lymphocytosis

Barilà, Gregorio; Calabretto, Giulia; Teramo, Antonella; Vicenzetto, Cristina; Gasparini, Vanessa Rebecca; Semenzato, Gianpietro; Zambello, Renato

doi:10.1016/j.beha.2019.06.006

Cited by 45 publications

(59 citation statements)

References 80 publications

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“…Of note, our CVID-ILD patients presented a significant expansion of CD3CD8CD57+ large T granular lymphocytes, in few patients recognized as T-LGLL; this might be related to splenomegaly/splenectomy, but the same population and T-LGLL itself are known to be related to autoimmune rather than cancer-related manifestations and deserves further investigation (31).…”

Section: Discussionmentioning

confidence: 76%

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

et al. 2021

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Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis.Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD.Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97).Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.

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Section: Discussionmentioning

confidence: 76%

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

et al. 2021

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“…In a personalized and precision medicine perspective, a search in the Drug Gene Interaction Database, identified that for at least six of the genes with validated variants (RPS6KA1, PIK3R1, TAOK2, TNFRSF1A, and TET2) one or more FDA-approved drugs are already available ( Table 2). For instance, cyclophosphamide interacts with TNFRSF1A and is already used in clinical management of T-LGLL as first line of treatment 44 , whereas hypomethylating agents (azacitidine and decitabine) are used to counteract TET2 loss of function, in myeloproliferative disorders 45 and the CDK inhibitor purvalanol A was shown to interact with RPS6KA1 46 .…”

Section: Discussionmentioning

confidence: 99%

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

et al. 2020

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The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.

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“…39 About 5% of the LGL leukemia patients suffer from a concurrent myelodysplastic syndrome. 7,13 These patients display a high prevalence of TET2, ASXL1, and DNMT3A mutations -suggesting that myelodysplasia and LGL leukemia could arise from a common CHIP. 38,40 Although NK ontogeny has been considered to be exclusively lymphoid, several studies have shown that NK cells may originate from myeloid progenitors.…”

Section: Stat3-and Tet2-mutated Clpd-nk Have Distinct Clinical and Phenotypical Patternsmentioning

confidence: 99%

“…2,3,4,5 Unlike T-LGL leukemias which are characterized by a clonal T-cell receptor (TCR) rearrangement, NK cell proliferations do not display TCR clonality, making the differential diagnosis between clonal CLPD-NK and reactive NK cell expansion challenging. 6,7 Indeed, after viral infection, autoimmune disease or organ transplantation, some patients have an elevated circulating LGL count, which raises the question of a reactive or neoplastic origin and highlights the need for an unambiguous diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells

Pastoret

Desmots

Drillet

et al. 2021

Blood

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Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK cell expansions is challenging. We assessed the value of NK receptor phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (N=46) and a reactive NK group (N=68). We then developed a NK-clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the CLPD-NK patients - constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK exhibited preferentially a CD16low phenotype, displayed more frequently a lower platelet count, and were associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed a whole exome sequencing of sorted, myeloid, T, and NK cells and identified that TET2 mutations were shared by myeloid and NK cells in 3 out of 4 cases. Thus, we hypothesized that TET2 alterations occur early in CLPD-NK disease which could explain a potential link between NK-LGL leukemia and other myeloid malignancies. Finally, we analyzed the transcriptome by RNA-seq of 7 CLPD-NK and evidenced two groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including two TET2-mutated cases, significantly under-expressed genes known to be down-regulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK cell proliferative disorders and potentially new therapeutic opportunities.

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T cell large granular lymphocyte leukemia and chronic NK lymphocytosis

Cited by 45 publications

References 80 publications

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells

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