CCL22 Mutations Promote NK-cell Lymphoproliferative Disease

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a subtype of large granular lymphocyte leukemia and is typically an indolent disease. Mutations in genes such as STAT3 and TET2 occur in about one third of cases, but the genetic basis that underlies the other two thirds of cases remains unknown. To address this, Baer, Kimura, and colleagues conducted genomic and transcriptomic analyses to determine the genetic landscape of this disease as well as the underlying mechanisms of pathogenesis and revealed recurrent clonal mutations in the C-C chemokine–encoding gene CCL22. These mutations were shown to be somatic and were mutually exclusive of mutations in STAT genes but not of TET2 mutations. Other differentially expressed genes were observed in those cases with mutated CCL22 and included high CD56 expression, low CD16 expression, as well as alterations to genes important for cell-to-cell communication, immune cell maturation/activation, and dendritic cell (DC) maturation. Additional experiments showed that the effects of CCL22 mutations were not due to autocrine effects on proliferation but to altered signaling upon binding to CCR4, which is the known receptor for CCL22. Specifically, this altered receptor binding led to increased chemotaxis of CCR4⁺ immune cells upon recombinant mutant CCL22 treatment as well as a reduction in ERK phosphorylation. Furthermore, NK-cell proliferation was enhanced by CCL22 mutations in vivo, and upregulated chemokine signaling and DC migration were also observed. Moreover, CCL22 mutants increased the percentage of IL15-producing cells, including macrophages and plasmacytoid DCs that promote NK-cell proliferation, supporting that CCL22-mutant cells not only promote NK-cell proliferation but also contribute to a microenvironment that further supports this phenotype. In summary, this study defines a subset of CLPD-NK defined by CCL22 mutations that induce leukemogenic effects through changes to the microenvironment and elucidates a mechanism by which tumor formation is induced through gain-of-function chemokine mutations.

Baer C, Kimura S, Rana MS, Kleist AB, Flerlage T, Feith DJ, et al. CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk. Nat Genet 2022 May 5 [Epub ahead of print].

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