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

Autor:	Pastoret C; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Desmots F; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Drillet G; Service d'Hématologie Clinique, Centre Hospitalier Universitaire (CHU) de Rennes, Rennes, France., Le Gallou S; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Boulland ML; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France., Thannberger A; Service d'Hématologie Clinique, Hôpital de Saint Malo, Saint Malo, France., Doncker AV; Hôpital Privé Sévigné, Cesson-Sévigné, France., Salaun V; Laboratoire d'Hématologie and., Damaj GL; Service d'Hématologie Clinique, CHU de Caen Normandie, Caen, France., Veyrat-Masson R; Laboratoire d'Hématologie and., Tournilhac O; Service d'Hématologie Clinique, CHU de Clermont-Ferrand, Clermont-Ferrand, France; and., Moignet A; Service d'Hématologie Clinique, Centre Hospitalier Universitaire (CHU) de Rennes, Rennes, France.; Centre d'Investigation Clinique (CIC) 1414, Rennes, France., Pangault C; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Roussel M; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Fest T; Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France., Lamy T; INSERM, Unité Mixte de Recherche (UMR) 1236, Etablissement Français du sang Bretagne, Université Rennes 1, Rennes, France.; Service d'Hématologie Clinique, Centre Hospitalier Universitaire (CHU) de Rennes, Rennes, France.; Centre d'Investigation Clinique (CIC) 1414, Rennes, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Jun 10; Vol. 137 (23), pp. 3237-3250.
DOI:	10.1182/blood.2020006721
Abstrakt:	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. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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