Page 16 - Haematologica August 2018

Editorials
available. A haploidentical relative is a suitable alternative when an HLA-matched sibling is not available.
References
1. Salvatore D, Labopin M, Ruggeri A, et al. Outcomes of hematopoietic stem cell transplantation from unmanipulated haploidentical versus matched sibling donor in patients with acute myeloid leukemia in first complete remission with intermediate or high-risk cytogenetics: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2018;103(8): 1317-1328.
2. Robinson TM, Fuchs EJ, Zhang MJ, et al. Related donor transplants: has posttransplant cyclophosphamide nullified the detrimental effect of HLA mismatch? Blood Adv. 2018;2(11):1180-1186.
3. Kollman C, Spellman SR, Zhang MJ, et al. The effect of donor char- acteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127(2):260-267.
4. Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor older hematopoietic transplant recipients: an older-aged sib- ling or a young, matched unrelated volunteer? Blood. 2013;121(13): 2567-2573.
5. McCurdy SR, Zhang MJ, St. Martin A, et al. Effect of donor charac- teristics on haploidentical transplantation with posttransplant cyclophosphamide. Blood Adv. 2018;2(3):299-307.
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G-protein coupled receptor (GPCR) mutations in lymphoid malignancies: linking immune signaling activation and genetic abnormalities
Jose Angel Martinez-Climent
Division of Hematological Oncology, Center for Applied Medical Research, University of Navarra, IDISNA, CIBERONC, Pamplona, Spain
E-mail: jamcliment@unav.es doi:10.3324/haematol.2018.196998
Marginal-zone B-cell lymphomas of mucosa-asso- ciated lymphoid tissue (MALT) arise from a background of chronic microbial infections or autoimmune disorders at diverse extranodal sites.1,2 The best characterized examples are gastric MALT lymphoma following Helicobacter pylori infection, and salivary gland or thyroid MALT lymphomas developing in patients with Sjögren syndrome or Hashimoto thyroiditis, respective- ly.3,4 It is now accepted that such chronic microenviron- mental inflammation stimulates surface BCR, TLR and CD40 receptors in B lymphocytes that converge to acti- vate downstream NF-κB signaling, which leads to the local expansion of autoreactive B cells eventually suffer- ing malignant transformation through the acquisition of genetic changes.5 Among them, three hallmark chromoso- mal translocations, t(11;18)(q21;q21), t(14;18)(q32;q21) and t(1;14)(p22;q32), play a major part in MALT lym- phoma origination through dysregulating MALT1 enzy- matic activity that constitutively triggers the NF-κB path- way independently of antigenic stimuli.6-9 Other recurrent mutations in the MYD88, TBL1XR1, KLF2 and TNFAIP3 genes are similarly a consequence of chronic receptor stimulation and further promote NF-κB signaling, con- tributing to lymphoma transformation.10 A second signal- ing pathway recurrently found to be involved in marginal- zone lymphoma (MZL) pathogenesis is NOTCH, primari- ly including mutations in the C-terminal PEST domain of NOTCH2 and NOTCH1 genes that enhance the stability of intracellular protein domains after being triggered by microenvironmental interactions.5 Thus, both the active chronic immunological stimuli and the acquired genetic abnormalities have critical roles during the development of MALT lymphoma through dysregulating similar molec- ular mechanisms.
In this issue of the Journal, Moody et al. expand this intriguing oncogenic co-operation between immune
receptor signaling and genetic abnormalities in MALT lymphoma. They report the discovery of somatic muta- tions in the G-protein coupled receptors (GPCRs) GPR34 and CCR6 not previously reported in human malignan- cies.11 The Authors performed whole exome sequencing of 21 salivary gland and thyroid tumors, and also carried out sequencing analysis of 249 MALT lymphomas, to define distinct mutation profiles in tumors of various sites. Those of the salivary gland were characterized by fre- quent TBL1XR1 and GPR34 mutations, whereas CCR6 changes were found in MALT lymphomas at different locations. The majority of GPR34 and CCR6 mutations clustered in the cytoplasmic tail, potentially leading to truncated gain-of-function proteins enabling constitutive ligand-dependent receptor activation.12 Thus, a novel syn- ergistic mechanism between constitutively active NF-κB and GPCR signaling pathways is proposed to participate in the development of MALT lymphoma (Figure 1A).
G-protein coupled receptors are made up of a large superfamily of cell surface ligands that regulate and trans- mit extracellular signals across the plasma membrane to induce a range of cellular and physiological responses. Despite this diversity, however, their structure, activation, signaling and regulatory mechanisms are remarkably con- served. GPCRs contain seven transmembrane spanning a- helices linked by three intracellular and three extracellular loop regions, an extracellular amino-terminal domain, and an intracellular carboxyl tail. In response to ligand binding, the receptor undergoes conformational changes to couple and activate heterotrimeric G proteins (Ga, Gb and Gγ) at the plasma membrane that regulate downstream signaling effectors. To turn off the response, GPCR kinases are recruited to phosphorylate the receptor and prepare them for b-arrestin binding, which compete with G protein cou- pling and desensitize the G-protein-mediated signaling response.13 Aberrant receptor activity has been shown in
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