Page 18 - Haematologica August 2018

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Editorials
with GPR34 translocations or mutations were observed in the setting of autoimmune disorders,11,17 one can hypothe- size that increased amounts of lysophosphatidylserine generated in salivary gland and thyroid tissues affected by chronic inflammation could have stimulated GPR34 in surrounding B lymphocytes to progressively induce malig- nant transformation through the acquired GPR34 genetic lesions.
Chemokine receptor 6 (CCR6) is a chemokine receptor expressed on a variety of immune cells with a well-estab- lished role as a modulator of inflammation.19 Most CCR6 mutations reported by Moody et al. are also clustered within the C-terminal cytoplasmic tail, potentially result- ing in constitutive receptor triggering (Figure 1C). However, despite sharing the mutation pattern with GPR34, CCR6 is stimulated by a different ligand, chemokine CCL20, since the CCR6/CCL20 axis is involved in the function of several cell types, including memory B lymphocytes, helper and regulatory T cells, and dendritic cells.20 Of note, a number of CCR6 missense genetic variants within the C-terminal domain have been associated with the occurrence of autoimmune disorders (Crohn disease and rheumatoid arthritis), and functional assays have demonstrated that these polymorphisms con- ferred decreased basal and/or ligand-induced CCR6 signal- ing.21 In several other experimental models, CCL20 and CCR6 interaction promoted intestinal carcinogenesis driv- en by macrophage recruitment into the intestine, while disruption of CCL20-CCR6 binding inhibited cutaneous T-cell lymphoma dissemination.19 These intriguing data provide the basis on which to define the functional role of CCR6 deregulation in MALT lymphoma.
The C-terminal distribution of mutations in GPR34 and CCR6 is similar to that observed in two other oncogenic GPCRs: C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 4 (CCR4).22,23 One-third of patients with Waldenström macroglobulinemia (WM), a rare lymphoplasmacytic lymphoma characterized by the constitutive MYD88 L265P activating mutation, exhibit CXCR4 mutations, which are also typical of the WHIM syndrome, an autosomal dominant immunodeficiency characterized by chronic neutropenia, hypogammaglobu- linemia, recurrent infections, and myelokathexis.24 Functional characterization of WHIM-like mutations (i.e. S338X) in WM cells showed impaired CXCR4 receptor internalization following ligand binding, which led to enhanced AKT and ERK activation.25 Interestingly, such mutations promoted resistance to standard-of-care ibruti- nib (a Bruton tyrosine kinase inhibitor) in WM cells, sug- gesting that additional therapies including proteasome inhibitors or CXCR4 targeting molecules could be of clin- ical benefit.22 While WHIM-like mutations have rarely been described in MZLs, increased expression of CXCR4 is frequently observed in splenic, nodal and MALT lym- phomas, and a functional role of this Cxcr4 overexpres- sion triggered by constitutive BCR signaling has been shown in experimental MZL models.15,26 On the other hand, CCR4 gain-of-function mutations located within the C-terminal domain are common in clinically aggres- sive adult T-cell leukemia/lymphoma, functionally leading to impaired receptor internalization and increased cell migration toward the CCL17 and CCL22 ligands.23
Collectively, these data reveal the presence of functionally similar gain-of-function mutations in different GPCRs that are selectively observed in distinct lymphoid malignan- cies.
However, a different type of GPCR mutations has been recently reported in nodal MZL, an entity closely related to MALT lymphoma. Spina et al. used whole-exome sequenc- ing to identify novel mutations in G-protein coupled recep- tor 98 (GPR98) in 5 of 35 (14%) cases, all of which corre- sponded to missense changes in the large GPR98 extracel- lular N-terminus domain of 5800 amino acids (G1133E, K2010R, E2910Q, V2927G, K4232N).27 Interestingly, Usher syndrome type IIC, an autosomal recessive disorder char- acterized by congenital hearing loss and progressive retini- tis pigmentosa (OMIM 605472), is caused by similar mis- sense mutations and gene deletions within Calx-b extracel- lular GPR98 domains (i.e. Q2301X, S2764P, S2832X, I2906FS, M2931Fs)28 (Figure 1C). These data, together with the Usher syndrome phenotype developed by Gpr98 knock-out mice, suggest a loss-of-function role for extracel- lular GPR98 mutations that still has to be investigated. In line with these observations, two other GPCR members, the sphingosine-1-phosphate receptor 2 (S1PR2) and the P2Y receptor family member 8 (P2RY8), are recurrently mutated in germinal center (GC) mature B-cell lym- phomas, preferentially by loss-of-function changes in the transmembrane domains.29 Further underscoring a deregu- lated role of GPCR signaling in GC B-cell-derived tumors, loss-of-signaling mutations disrupting the GNA13 gene (encoding the Ga13 coupled protein transmitting S1PR2/P2RY8 receptor signaling) and its effector ARHGEF1 are also frequently observed, together delineat- ing a GPCR pathway that, when disrupted, promotes the growth and blocks the dissemination of GC B lympho- cytes to induce the development of GC B-cell lymphoma.29
In summary, there is increasing evidence to support the implication of GPCR mutations in the pathogenesis of several lymphoid malignancies. Different clinical-patho- logical entities show functionally similar C-terminal domain mutations in specific GPCRs that seem to impair receptor internalization and induce constitutive receptor signaling, including CXCR4 in WM, CCR6 in T-cell leukemia/lymphoma, and GPR34 and CCR6 in MALT lymphoma. Conversely, mutations in transmembrane or extracellular domains of other GPCRs can be considered loss-of-function mutations that impair downstream recep- tor signaling, including GPR98 in nodal MZL, and S1PR2 and P2RY8 in GC B-cell lymphomas. Such unique genetic and territorial associations strongly suggest a role of tis- sue-specific extracellular cues that activate selective GPCR function and disturb cell dynamics to progressively cause genetic lesions. The functional consequences of most of these genetic changes are largely unknown, particularly in the context of the obvious synergistic co-operation of spe- cific GPCR mutations with other selected genetic abnor- malities on each particular tumor type. Among them, co- existence of CXCR4 and MYD88 mutations is currently a critical issue in the diagnosis and therapy of patients with WM, while other associations such as GPR34 and TBL1XR1 mutations in MALT lymphomas of the salivary glands remain to be characterized. Looking beyond this, the present study by Moody et al. provides a new insight
haematologica | 2018; 103(8)