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

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of NK cells where the underlying genetic mechanisms are incompletely understood. Here, 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, were mutually exclusive of STAT3 mutations, and were 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 for CCL22, CCR4, via impaired β-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment, and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a unique mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased G-protein-coupled receptor signaling and dysregulation of microenvironmental crosstalk.