Page 99 - Haematologica August 2018

Novel GPCR mutation in MALT lymphoma
Figure 4. Significant association among genetic changes in mucosa-associated lymphoid tissue (MALT) lymphoma of the salivary gland and ocular adnexa. In both cohorts, samples lacking the described changes are not included. P-value in red: positive correlation; P-value in black: negative correlation; significant values are in bold; X: inactivating frameshift and nonsense mutations; D: deletion; s: splice site mutations; T: translocation.
report suggests that mutations enhance TBL1XR1 binding to NCoR and facilitate its degradation, consequently pro- moting NF-κB and JUN target gene expression.41 Thus, TBL1XR1 mutation may sustain GPR34 mediated NF-κB and AP1 activation via this mechanism.
Why GPR34 mutation and translocation are preferential- ly associated with MALT lymphoma of the salivary gland is unclear. GPR34 has been shown to be activated by lyso- phosphatidylserine, which could be generated by hydroly- sis of the exposed membrane lipids in apoptotic cells through phospholipase A.37,38 Among MALT lymphoma of various sites, the lymphoepithelial lesions are most promi- nent in those of salivary gland. It remains to be investigat- ed whether such lymphoepithelial lesions may facilitate the production of lyso-phosphatidylserine, the ligand for GPR34, thereby facilitating the expansion and localization of B cells carrying GPR34 genetic changes surrounding the lymphoepithelial lesion.
In MALT lymphoma of the ocular adnexa, TBL1XR1 mutation is mutually exclusive from TNFAIP3 mutation and IGHV4-34 usage, but significantly associated with IGHV3- 23 usage and PIK3CD mutation, albeit with limited num- bers of cases involved. Like IGHV4-34 rearrangements, the IGHV3-23 rearrangement seen in ocular adnexal MALT lymphoma also encodes autoreactive BCR as shown by recombinant antibody studies.5 In this context, the signifi-
cant association between TBL1XR1 mutation and IGHV3- 23 rearrangement is very much analogous to that between TNFAIP3 mutation and IGHV4-34 rearrangement reported previously,17 hence expanding the evidence supporting oncogenic co-operation between antigenic drive and acquired genetic changes in MALT lymphoma. Similarly, the significant association between TBL1XR1 and PIK3CD mutation may also signify oncogenic co-operation between the two genetic events.
In summary, our study reveals several novel genetic changes including GPR34 and CCR6 mutations not yet reported in human malignancies, and provides further evi- dence of distinct mutation profiles in MALT lymphoma of various sites. These novel findings offer exciting prospects for further characterization of the molecular pathogenesis of MALT lymphoma.
Acknowledgments
The authors would like to thank David Withers, Cambridge Genomics Services and Graeme Clark (Medical Genetics) for technical assistance with sequencing. The research was supported by grants from Bloodwise (13006, 15002, 15019), UK, and the Kay Kendal Leukaemia Fund (KKL582), UK. SM was initially supported by a PhD studentship from the Medical Research Council, Department of Pathology, University of Cambridge and Addenbrooke’s Charitable Trust, UK.
haematologica | 2018; 103(8)
1335