A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
22 04 2020
22 04 2020
Historique:
received:
27
11
2019
accepted:
03
04
2020
revised:
24
03
2020
entrez:
24
4
2020
pubmed:
24
4
2020
medline:
2
12
2020
Statut:
epublish
Résumé
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 PIK3R1-negative 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.
Identifiants
pubmed: 32321919
doi: 10.1038/s41408-020-0309-2
pii: 10.1038/s41408-020-0309-2
pmc: PMC7176632
doi:
Substances chimiques
Biomarkers, Tumor
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
42Subventions
Organisme : Sigrid Juséliuksen Säätiö (Sigrid Jusélius Foundation)
ID : M-IMM
Pays : International
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG 20216
Pays : International
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG 20052
Pays : International
Organisme : Fondazione Cassa di Risparmio di Padova e Rovigo (Foundation Cariparo)
ID : PREMED-AL and CELL
Pays : International
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : 2017PPS2X4_003
Pays : International
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