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

Constance Baer, Shunsuke Kimura, Mitra S. Rana, Andrew B. Kleist, Tim Flerlage, David J. Feith, Peter Chockley, Wencke Walter, Manja Meggendorfer, Thomas L. Olson, Hee Jin Cheon, Kristine C. Olson, Aakrosh Ratan, Martha Lena Mueller, James M. Foran, Laura J. Janke, Chunxu Qu, Shaina N. Porter, Shondra M. Pruett-Miller, Ravi C. KalathurClaudia Haferlach, Wolfgang Kern, Elisabeth Paietta, Paul G. Thomas, M. Madan Babu, Thomas P. Loughran, Ilaria Iacobucci, Torsten Haferlach, Charles G. Mullighan

Research output: Contribution to journalArticlepeer-review

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 CD16dim/CD56bright 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 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 GPCR signaling and dysregulation of microenvironmental crosstalk.

Original languageEnglish (US)
Pages (from-to)637-648
Number of pages12
JournalNature Genetics
Volume54
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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