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

被引：33

作者：

Baer, Constance ^{[1
]}

Kimura, Shunsuke ^{[2
]}

Rana, Mitra S. ^{[3
]}

Kleist, Andrew B. ^{[4
,5
]}

Flerlage, Tim ^{[6
]}

Feith, David J. ^{[7
,8
]}

Chockley, Peter ^{[9
]}

Walter, Wencke ^{[1
]}

Meggendorfer, Manja ^{[1
]}

Olson, Thomas L. ^{[7
,8
]}

Cheon, HeeJin ^{[7
,8
,10
]}

Olson, Kristine C. ^{[7
,8
]}

Ratan, Aakrosh ^{[7
,10
,11
]}

Mueller, Martha-Lena ^{[1
]}

Foran, James M. ^{[12
]}

Janke, Laura J. ^{[2
]}

Qu, Chunxu ^{[2
]}

Porter, Shaina N. ^{[13
]}

Pruett-Miller, Shondra M. ^{[13
]}

Kalathur, Ravi C. ^{[3
]}

Haferlach, Claudia ^{[1
]}

Kern, Wolfgang ^{[1
]}

Paietta, Elisabeth ^{[14
]}

Thomas, Paul G. ^{[15
]}

Babu, M. Madan ^{[16
]}

Loughran, Thomas P. ^{[7
,8
]}

Iacobucci, Ilaria ^{[2
]}

Haferlach, Torsten ^{[1
]}

Mullighan, Charles G. ^{[2
,17
]}

机构：

[1] MLL Munich Leukemia Lab, Munich, Germany

[2] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Struct Biol, Prot Technol Ctr, 332 N Lauderdale St, Memphis, TN 38105 USA

[4] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

[5] Med Coll Wisconsin, Med Scientist Training Program, Milwaukee, WI 53226 USA

[6] St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA

[7] Univ Virginia, Ctr Canc, Charlottesville, VA 22908 USA

[8] Univ Virginia, Sch Med, Dept Med, Div Hematol Oncol, Charlottesville, VA 22908 USA

[9] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cell Therapy, 332 N Lauderdale St, Memphis, TN 38105 USA

[10] Univ Virginia, Sch Med, Med Scientist Training Program, Charlottesville, VA 22908 USA

[11] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA

[12] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[13] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[14] Montefiore Med Ctr, Dept Oncol, 111 E 210Th St, Bronx, NY 10467 USA

[15] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA

[16] St Jude Childrens Res Hosp, Ctr Excellence Data Driven Discovery, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[17] St Jude Childrens Res Hosp, Hematol Malignancies Program, 332 N Lauderdale St, Memphis, TN 38105 USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 05期

关键词：

CHEMOKINE RECEPTOR CCR4; CD56(BRIGHT) NK CELLS; REGULATORY T-CELLS; DENDRITIC CELLS; STAT3; MUTATIONS; RETICULAR CELLS; IL-15; LEUKEMIA; SUBSET; INTERNALIZATION;

D O I：

10.1038/s41588-022-01059-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 beta-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. Genomic and transcriptomic analyses of chronic lymphoproliferative disorder of natural killer cells identifies somatic gain-of-function mutations in the chemokine gene CCL22 with cell-extrinsic effects. Mutations caused biased signaling downstream of the G-protein-coupled receptor for CCL22 and deregulated interactions with the hematopoietic microenvironment.

引用

页码：637 / +

页数：31

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