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. Kalathur; Claudia Haferlach; Wolfgang Kern; Elisabeth Paietta; Paul G. Thomas; M. Madan Babu; Thomas P. Loughran; Ilaria Iacobucci; Torsten Haferlach; Charles G. Mullighan

doi:10.1038/s41588-022-01059-2

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

Oncology

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11 Scopus citations

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 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 language	English (US)
Pages (from-to)	637-648
Number of pages	12
Journal	Nature Genetics
Volume	54
Issue number	5
DOIs	https://doi.org/10.1038/s41588-022-01059-2
State	Published - May 2022

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Genetics

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Baer, C., Kimura, S., Rana, M. S., Kleist, A. B., Flerlage, T., Feith, D. J., Chockley, P., Walter, W., Meggendorfer, M., Olson, T. L., Cheon, H. J., Olson, K. C., Ratan, A., Mueller, M. L., Foran, J. M., Janke, L. J., Qu, C., Porter, S. N., Pruett-Miller, S. M., ... Mullighan, C. G. (2022). CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk. Nature Genetics, 54(5), 637-648. https://doi.org/10.1038/s41588-022-01059-2

Baer, C, Kimura, S, Rana, MS, Kleist, AB, Flerlage, T, Feith, DJ, Chockley, P, Walter, W, Meggendorfer, M, Olson, TL, Cheon, HJ, Olson, KC, Ratan, A, Mueller, ML, Foran, JM, Janke, LJ, Qu, C, Porter, SN, Pruett-Miller, SM, Kalathur, RC, Haferlach, C, Kern, W, Paietta, E, Thomas, PG, Babu, MM, Loughran, TP, Iacobucci, I, Haferlach, T & Mullighan, CG 2022, 'CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk', Nature Genetics, vol. 54, no. 5, pp. 637-648. https://doi.org/10.1038/s41588-022-01059-2

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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 = "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)",

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T1 - CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk

AU - Baer, Constance

AU - Kimura, Shunsuke

AU - Rana, Mitra S.

AU - Kleist, Andrew B.

AU - Flerlage, Tim

AU - Feith, David J.

AU - Chockley, Peter

AU - Walter, Wencke

AU - Meggendorfer, Manja

AU - Olson, Thomas L.

AU - Cheon, Hee Jin

AU - Olson, Kristine C.

AU - Ratan, Aakrosh

AU - Mueller, Martha Lena

AU - Foran, James M.

AU - Janke, Laura J.

AU - Qu, Chunxu

AU - Porter, Shaina N.

AU - Pruett-Miller, Shondra M.

AU - Kalathur, Ravi C.

AU - Haferlach, Claudia

AU - Kern, Wolfgang

AU - Paietta, Elisabeth

AU - Thomas, Paul G.

AU - Babu, M. Madan

AU - Loughran, Thomas P.

AU - Iacobucci, Ilaria

AU - Haferlach, Torsten

AU - Mullighan, Charles G.

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

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JO - Nature Genetics

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

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