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, HeeJin 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 Kalathur, Claudia Haferlach, Wolfgang Kern, Elisabeth Paietta, Paul G Thomas, M Madan Babu, Thomas P Loughran, Ilaria Iacobucci, Torsten Haferlach, Charles G Mullighan
Nature genetics 2022 MayChronic 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. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Citation
Constance Baer, Shunsuke Kimura, Mitra S Rana, Andrew B Kleist, Tim Flerlage, David J Feith, Peter Chockley, Wencke Walter, Manja Meggendorfer, Thomas L Olson, HeeJin 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 Kalathur, Claudia Haferlach, Wolfgang Kern, Elisabeth Paietta, Paul G Thomas, M Madan Babu, Thomas P Loughran, Ilaria Iacobucci, Torsten Haferlach, Charles G Mullighan. CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk. Nature genetics. 2022 May;54(5):637-648
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PMID: 35513723
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