Page 17 - Haematologica August 2018

Editorials
numerous disorders including cancer, ranging from dereg- ulated patterns of expression in particular tumor entities to pathogenic gene mutations potentially contributing to malignant transformation.14,15 Consequently, GPCR phar- macological targeting is under development for a variety of indications such as inflammation, neurobiological and metabolic disorders, and cancer.14,16
The discovery of G-protein coupled receptor 34 (GPR34) mutations in MALT lymphoma is not totally unexpected, as deregulation of the GPR34 gene through juxtaposition to IGVH gene sequences has already been reported after the molecular cloning of a recurrent t(X;14)(p11;q32) chromosomal translocation.17 Elevated GPR34 expression was detected independently of the translocation in most other MALT lymphoma cases, lead- ing to increased proliferation through constitutive activa-
A
tion of the ERK and NF-κB pathways.17 In line with this gain-of-function oncogenic potential, the majority of GPR34 mutations identified by Moody et al. are nonsense or frameshift changes clustered in the C-terminal region, resulting in truncated proteins that would eliminate or impair a key phosphorylation motif and thus deregulate the receptor desensitization process (Figure 1B).12 The remaining GPR34 mutations are missense changes includ- ing Y327N, which locates in between the transmembrane domain and the cytoplasmic tail, and R84H and D151A at the intracellular loops, which also seem to induce consti- tutive receptor signaling activation.12,18 Lysophosphatidylserine, an endogenous lipid mediator generated by the hydrolysis of the membrane phospho- lipid phosphatidylserine, has been proposed as one of the ligands of GPR34.18 Because most MALT lymphoma cases
B
C
Figure 1. G-protein coupled receptor (GPCR) mutations co-operate with con- stitutively active NF-κB and NOTCH sig- naling pathways in mucosa-associated lymphoid tissue (MALT) lymphoma. (A) Representation of major signaling path- ways affected by somatic genetic changes in patients with MALT lym- phoma. (B) Schematic representation of GPR34 and CCR6 C-terminal mutant isoforms in MALT lymphoma (according to Moody et al.11). (C) GPR98 mutations in the extracellular domain in nodal MZL (as reported by Spina et al.27).
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