STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells

Kawakami, Toru; Sekiguchi, Nodoka; Kobayashi, Jun; Yamane, Taku; Nishina, Sayaka; Sakai, Hitoshi; Hirabayashi, Yukio; Nakazawa, Hayakazu; Ishida, Fumihiro

doi:10.1007/s12185-019-02625-x

Cited by 23 publications

(25 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since this disease is rarer than the T related entity, less data are available and appropriate analyses are lacking to precisely define this disorder. The similarity with T-LGLL involves STAT3 gene, that is reported mutated also in CLPD-NK [ (17,38); Figure 1]. To note, our data indicate that STAT3 mutations seem to have a lower incidence, from 5.9 to 8.3%, in this disease as compared to T-LGLL (15,39).…”

Section: Stat3 and Stat5b Mutationssupporting

confidence: 59%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

View full text Add to dashboard Cite

Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

show abstract

Section: Stat3 and Stat5b Mutationssupporting

confidence: 59%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…JAK/STAT mutations or amplifications were shown to be involved in ANKL 11 and NKTCL 12 as well, although with a lower prevalence as compared to T-LGLL. Genes of the JAK/STAT pathway reported to be associated to CLPD-NK (STAT3, STAT5B, and JAK3) 14,15 were not mutated in the 13 patients analyzed by WES. Mutations of TNFAIP3 15 , previously found in CLPD-NK, were not detected in our cohort.…”

Section: Discussionmentioning

confidence: 93%

“…Only scattered data are available on the molecular features underlying CLPD-NK, mainly provided by approaches targeted to exons of specific genes, with limited discovery power. STAT3 mutations were almost all identified in exons 20-21 encoding the Src homology 2 domain, with different prevalence in different cohorts 7,[14][15][16] . Albeit relatively rare, STAT3 mutations are regarded as a diagnostic tool, in addition to the aberrant NK-cell immunophenotype and bone marrow or splenic infiltration by cytotoxic lymphocytes 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Albeit relatively rare, STAT3 mutations are regarded as a diagnostic tool, in addition to the aberrant NK-cell immunophenotype and bone marrow or splenic infiltration by cytotoxic lymphocytes 14 . CLPD-NK patients with STAT3 mutations often require treatment and STAT3 mutations have been found to correlate with a CD3− CD16+ CD56 dim CD57− immunophenotype 16 and cytopenias, such as anemia 15 or severe neutropenia 16 . STAT5B, a gene essential for NK cell biology 17 and frequently mutated in CD4+ T-LGL leukemia 18 , has been found mutated only in one patient diagnosed with CLPD-NK (3%), who later progressed to ANKL 9 .…”

Section: Introductionmentioning

confidence: 99%

“…STAT5B, a gene essential for NK cell biology 17 and frequently mutated in CD4+ T-LGL leukemia 18 , has been found mutated only in one patient diagnosed with CLPD-NK (3%), who later progressed to ANKL 9 . Somatic mutations in few other genes of the JAK/ STAT pathway, such as JAK3 (10%) 14 , and of the NFkappa B signaling pathway, such as TNFAIP3 (6%) 15 , were seldom detected in CLPD-NK.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations

et al. 2020

View full text Add to dashboard Cite

Large granular lymphocyte (LGL) leukemia is a rare hematological disorder with expansion of the T‐cell or natural killer (NK) cell lineage. Signal transducer and activator of transcription 3 (STAT3) exhibits somatic activating mutations in 30%‐40% of LGL leukemia cases. Transcriptional targets of STAT3 include inflammatory cytokines, thus previous studies have measured cytokine levels of LGL leukemia patients compared to normal donors. Sphingolipid metabolism is a growing area of cancer research, with efforts focused on drug discovery. To date, no studies have examined serum sphingolipids in LGL leukemia patients, and only one study compared a subset of cytokines between the T‐LGL and NK‐LGL subtypes. Therefore, here, we included both LGL leukemia subtypes with the goals of (a) measuring serum sphingolipids for the first time, (b) measuring cytokines to find distinctions between the subtypes, and (c) establishing relationships with STAT3 mutations and clinical data. The serum analyses identified cytokines (EGF, IP‐10, G‐CSF) and sphingolipids (SMC22, SMC24, SMC20, LysoSM) significantly different in the LGL leukemia group compared to normal donors. In a mixed STAT3 mutation group, D661Y samples exhibited the highest mean corpuscular volume (MCV) values. We explored this further by expanding the cohort to include larger groups of single STAT3 mutations. Male D661Y STAT3 samples had lower Hgb and higher MCV compared to wild type (WT) or Y640F counterparts. This is the first report examining large groups of individual STAT3 mutations. Overall, our results revealed novel serum biomarkers and evidence that D661Y mutation may show different clinical manifestation compared to WT or Y640F STAT3.

show abstract

STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells

Cited by 23 publications

References 21 publications

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

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

Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations

Contact Info

Product

Resources

About