Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells.
Aged
Chronic Disease
DNA-Binding Proteins
/ genetics
Dioxygenases
/ genetics
Female
Hematopoietic Stem Cells
/ metabolism
Humans
Killer Cells, Natural
/ metabolism
Lymphoma, T-Cell
/ genetics
Male
Middle Aged
Mutation
Neoplasm Proteins
/ genetics
Receptors, KIR
/ genetics
STAT3 Transcription Factor
/ genetics
KIR phenotype
NEOPLASIA/Lymphomas and Other Lymphoproliferative Conditions: genetic and other predisposing conditions
STAT3
TET2
chronic lymphoproliferative disorder of NK cells
large granular lymphocyte leukemia
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
10 06 2021
10 06 2021
Historique:
received:
29
04
2020
accepted:
16
12
2020
pubmed:
30
1
2021
medline:
15
12
2021
entrez:
29
1
2021
Statut:
ppublish
Résumé
Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) 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 an NK-cell 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 patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities.
Identifiants
pubmed: 33512451
pii: S0006-4971(21)00115-4
doi: 10.1182/blood.2020006721
pmc: PMC8351897
doi:
Substances chimiques
DNA-Binding Proteins
0
Neoplasm Proteins
0
Receptors, KIR
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Dioxygenases
EC 1.13.11.-
TET2 protein, human
EC 1.13.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3237-3250Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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