@article{74767040b69141e2bfb6ba472f6802d0,
title = "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 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.",
author = "Constance Baer and Shunsuke Kimura and Rana, {Mitra S.} and Kleist, {Andrew B.} and Tim Flerlage and Feith, {David J.} and Peter Chockley and Wencke Walter and Manja Meggendorfer and Olson, {Thomas L.} and Cheon, {Hee Jin} and Olson, {Kristine C.} and Aakrosh Ratan and Mueller, {Martha Lena} and Foran, {James M.} and Janke, {Laura J.} and Chunxu Qu and Porter, {Shaina N.} and Pruett-Miller, {Shondra M.} and Kalathur, {Ravi C.} and Claudia Haferlach and Wolfgang Kern and Elisabeth Paietta and Thomas, {Paul G.} and Babu, {M. Madan} and Loughran, {Thomas P.} and Ilaria Iacobucci and Torsten Haferlach and Mullighan, {Charles G.}",
note = "Funding Information: We thank the American and Lebanese Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital and the National Cancer Institute of the NIH for their support under award nos. P30 CA021765, R35 CA197695 (to C.G.M.), R01 CA178393 and P30 CA044579 (to T.P.L.), UG1CA189859, U10CA180820 and UG1CA232760 (to J.F. and E.P.) and F30CA196040 (to A.B.K.); the National Institute of General Medical Sciences grant no. T32 GM080202 (to A.B.K.); the National Library of Medicine grant no. T32 LM012416 (to H.C.); the Henry Schueler 41 & 9 Foundation (to C.G.M.); a St. Baldrick{\textquoteright}s Foundation Robert J. Arceci Innovation Award (to C.G.M.); a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St. Jude Children{\textquoteright}s Research Hospital Comprehensive Cancer Center (to S.K.); and the Bess Family Charitable Fund, the LGL Leukemia Foundation and a generous anonymous donor (to T.P.L.). We thank ECOG-ACRIN Cancer Research Group for acute NK leukemia samples. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank: S. Surman (Department of Infectious Diseases, St. Jude) for flow cytometry; B. Shemo for LGL Leukemia Registry support; M. Schmachtenberg for technical support; and S. Onengut-Gumuscu and E. Farber for targeted sequencing of the validation cohort at the University of Virginia. Funding Information: We thank the American and Lebanese Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital and the National Cancer Institute of the NIH for their support under award nos. P30 CA021765, R35 CA197695 (to C.G.M.), R01 CA178393 and P30 CA044579 (to T.P.L.), UG1CA189859, U10CA180820 and UG1CA232760 (to J.F. and E.P.) and F30CA196040 (to A.B.K.); the National Institute of General Medical Sciences grant no. T32 GM080202 (to A.B.K.); the National Library of Medicine grant no. T32 LM012416 (to H.C.); the Henry Schueler 41 & 9 Foundation (to C.G.M.); a St. Baldrick{\textquoteright}s Foundation Robert J. Arceci Innovation Award (to C.G.M.); a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St. Jude Children{\textquoteright}s Research Hospital Comprehensive Cancer Center (to S.K.); and the Bess Family Charitable Fund, the LGL Leukemia Foundation and a generous anonymous donor (to T.P.L.). We thank ECOG-ACRIN Cancer Research Group for acute NK leukemia samples. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank: S. Surman (Department of Infectious Diseases, St. Jude) for flow cytometry; B. Shemo for LGL Leukemia Registry support; M. Schmachtenberg for technical support; and S. Onengut-Gumuscu and E. Farber for targeted sequencing of the validation cohort at the University of Virginia. Funding Information: C.B., W.W., M.M. and M.L.M. are employed by MLL Munich Leukemia Laboratory. C.H., W.K. and T.H. have equity ownership of MLL Munich Leukemia Laboratory. I.I. received honoraria from Amgen and Mission Bio. C.G.M. received research funding from Loxo Oncology, Pfizer and AbbVie, and honoraria from Amgen and Illumina, and holds stock in Amgen. T.P.L. is on the Scientific Advisory Board and has stock options for Keystone Nano, Bioniz Therapeutics and Dren Bio. T.P.L. and D.J.F. received honoraria from Kymera Therapeutics. D.J.F. has research funding from AstraZeneca. There are no conflicts of interest with the work presented in this manuscript. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = may,
doi = "10.1038/s41588-022-01059-2",
language = "English (US)",
volume = "54",
pages = "637--648",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}