CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.

ABSTRACT: Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16^dim/CD56^bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor (GPCR) for CCL22, CCR4, via impaired β-arrestin recruitment. This resulted in increased cell chemot

SUBMITTER: Baer C 

PROVIDER: S-EPMC9117519 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature