美国圣犹大儿童研究医院Charles G. Mullighan，Ilaria Iacobucci和Shunsuke Kimura以及德国慕尼黑白血病实验室Torsten Haferlach共同合作取得重要工作进展，他们研究发现CCL22突变通过解除对微环境串扰的调控来驱动自然杀伤细胞淋巴增生性疾病。该项研究成果2022年5月5日在线发表于《自然—遗传学》杂志上。

在本研究中，研究人员报告了趋化因子基因CCL22中的体细胞突变作为CLPD-NK不同子亚群的标志。CCL22突变富含高度保守的残基，与STAT3突变互斥，并与类似于正常CD16dim/CD56bright NK细胞的基因表达程序相关。从机制上讲，突变导致配体偏向的趋化因子受体信号传导，通过受损的β-抑制蛋白募集，CCL22、CCR4的G蛋白偶联受体 (GPCR) 的内化减少。这导致细胞在体外的趋化性增加，与造血微环境的双向串联，以及在转基因人类IL-15小鼠体内的NK细胞增殖增强。

体细胞CCL22突变说明了一种独特的肿瘤形成机制，其中功能获得性趋化因子突变通过偏向的GPCR信号传导和微环境串扰的失调促进肿瘤发生。

据了解，自然杀伤细胞慢性淋巴增生性疾病 (CLPD-NK) 的特征是自然杀伤 (NK) 细胞的克隆扩增，其中潜在的遗传机制尚不完全清楚。

附：英文原文

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

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

Issue&Volume: 2022-05-05

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.

DOI: 10.1038/s41588-022-01059-2

Source: https://www.nature.com/articles/s41588-022-01059-2