Casato, Milvia

Visentini, Marcella

English

Marcella Visentini

Milvia Casato

Archivio della ricerca- Università di Roma La Sapienza

Conflict-of-interest disclosure: The authordeclares no competing financial interests. nREFERENCES1. Busygina K, Jamasbi J, Seiler T, et al. OralBruton tyrosine kinase inhibitors selectivelyblock atherosclerotic plaque–triggeredthrombus formation in humans. Blood. 2018;131(24):2605-2616.2. Steg PG, Dorman SH, Amarenco P.Atherothrombosis and the role of antiplatelettherapy. J ThrombHaemost. 2011;9(9 suppl 1):325-332.3. Shim CY, Liu YN, Atkinson T, et al. Molecularimaging of platelet-endothelial interactionsand endothelial von Willebrand factor inearly and mid-stage atherosclerosis. CircCardiovasc Imaging. 2015;8(7):e002765.4. Quek LS, Bolen J, Watson SP. A role forBruton’s tyrosine kinase (Btk) in platelet acti-vation by collagen. Curr Biol. 1998;8(20):1137-1140.5. Kamel S, Horton L, Ysebaert L, et al. Ibrutinibinhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia.2015;29(4):783-787.6. Shatzel JJ, Olson SR, Tao DL, McCarty OJT,Danilov AV, DeLoughery TG. Ibrutinib-associated bleeding: pathogenesis, man-agement and risk reduction strategies.J Thromb Haemost. 2017;15(5):835-847.7. Massberg S, Gawaz M, Gru¨ner S, et al.A crucial role of glycoprotein VI for plateletrecruitment to the injured arterial wall in vivo.J Exp Med. 2003;197(1):41-49.8. Nigro P, Abe J, Berk BC. Flow shear stress andatherosclerosis: a matter of site specificity.Antioxid Redox Signal. 2011;15(5):1405-1414.9. Virmani R, Kolodgie FD, Burke AP, et al.Atherosclerotic plaque progression andvulnerability to rupture: angiogenesis asa source of intraplaque hemorrhage.Arterioscler Thromb Vasc Biol. 2005;25(10):2054-2061.10. Brown JR, Moslehi J, O’Brien S, et al.Characterization of atrial fibrillation adverseevents reported in ibrutinib randomized con-trolled registration trials. Haematologica.2017;102(10):1796-1805.DOI 10.1182/blood-2018-04-841916© 2018 by The American Society of HematologyLYMPHOID NEOPLASIAComment on Ren et al, page 2670HBV messing with the B-cellgenome leads to DLBCLMarcella Visentini and Milvia Casato | Sapienza University of Rome MedicalSchoolIn this issue of Blood, Ren et al report the results of a broad genomic andtranscriptomic analysis of hepatitis B virus (HBV)–associated diffuse largeB-cell lymphomas (DLBCLs) in Chinese patients, providing for the first time adistinctive molecular profile of these tumors.1Among the 275 DLBCL samples charac-terizedbywhole-genome sequencing andwhole-exome sequencing, 20%were fromHBV infection surface antigen–positive(HBsAg1) patients. This high proportion,related to endemic HBV in China, providesa unique opportunity for investigating dif-ferences in clinical and mutational spec-tra between HBV-related and -unrelatedDLBCL in the context of a common ethnicbackground. HBsAg1 DLBCL patientscompared with HBsAg– patients hadsignificantly younger age, more aggres-sive disease, and shorter survival, similarto the findings in another study in Chinesepatients.2 Genome-wide analysis revealedan increased total mutation load in HBsAg1DLBCL possibly resulting from APOBECenzyme activity and also a distinctive setof mutated genes that might be related tothe activity of the B-cell–specific activation-induced cytidine deaminase (AID). BCL6was the lymphoma-related gene most fre-quently mutated (79%) in HBsAg1DLBCL,together with other genes involved in theFOXO signaling pathway (CXCR4, KLF2,and SGK1). The authors speculate thatalterations of the FOXO pathway mightpromote the development of HBsAg1DLBCL by inducing antigen-independenttonic B-cell receptor signaling, and theysuggest BCL6 as an important therapeutictarget.HBV and hepatitis C virus (HCV) sharehepatotropism and the capacity to induceB-cell lymphomas.3 In the case of HCV,it is generally agreed that lymphomasdevelop as a consequence of the pro-tracted stimulation of B cells expressingspecific stereotyped idiotypes putativelydirected to a viral antigen that has not yetbeen identified.4 A major argument infavor of this hypothesis is the frequentregression of indolent lymphomas asso-ciated with HCV, but not with HCV1DLBCL, after the clearance of infectionwith antiviral therapy.5 Ren et al char-acterized the V(D)J region of immuno-globulin (Ig) heavy chain in 15 HBsAg1DLBCL samples and were unable to iden-tify recurrent stereotyped idiotypes. Thiscontrasts with another study2 in HBsAg1DLBCL Chinese patients that identified 2stereotyped sequences in 4 of 16 patientsstudied and claimed significant homologyof these antibodies to antibodies specificfor HBsAg.On the basis of their results, Ren et alrejected the hypothesis that HBV, likeHCV, causes lymphomas by protractedantigenic stimulation of B cells that pro-duce virus-specific antibodies and sug-gest that infection of B cells by HBV mayinduce a hyperactive status that leads toenhanced mutagenesis mediated in partby APOBEC and AID. Indeed, these2 hypotheses might not necessarily bemutually exclusive. In the case of HCV, forwhich an antigen-driven mechanism oflymphomagenesis is generally accepted,it has also been shown6 that infection ofB cells by the virus induces a mutatorphenotype that leads to a five- to 10-foldincrease in mutation frequency in BCL6,Ig heavy chain, and p53 genes. Con-versely, it is also known that some HBV-infected individuals develop type 2 mixedcryoglobulinemia, a monoclonal B-cell lym-phoproliferative disorder that can regressafter infection is suppressed by antiviraltherapy.7 This suggests antigenic pressureas the cause of monoclonal lympho-proliferation because that is the case forHCV-related mixed cryoglobulinemia.HCV causes a large spectrum of lympho-proliferative disorders ranging from themost frequent mixed cryoglobulinemia,which is benign but highly prone toneoplastic evolution, to indolent lym-phomas mainly originating frommarginalzone B cells, to aggressive DLBCL. Thissuggests that evolution from benignmonoclonal lymphoproliferation to aggres-sive lymphoma may be driven by continualantigenic stimulation and accumulation ofmutations. By contrast, HBV rarely causesmixed cryoglobulinemia, andHBV-relatedindolent lymphomas are much rarer than2602 blood® 14 JUNE 2018 | VOLUME 131, NUMBER 24For personal use only.on June 20, 2018. by guest  www.bloodjournal.orgFrom HBV-related DLBCL in Chinese patients.8This large predominance of DLBCL overindolent lymphoproliferative disorderssupports a model of HBV-driven muta-genesis directly leading to DLBCL ratherthan that of stimulation-driven progres-sion from indolent to aggressive forms.HBV-driven mutagenesis might occur bya hit-and-run mechanism, because Renet al could not detect any HBV DNA in-tegrated into DLBCL cells. Nevertheless,the continual antigenic stimulation modelstill stands as themost likely explanation forHBV-dependent mixed cryoglobulinemia(see figure).The large body of data from Ren’s studyprovides a framework for decipheringthe mechanisms by which HBV altersthe B-cell genome up to development ofDLBCL and, importantly, identifies potentialtherapeutic targets for these aggressive tu-mors. Future studies should clarify whetherthe distinctive molecular signatures foundin HBsAg1 DLBCL Chinese patients arealso present in patients of Western origin.In addition, the issue of whether virus-specific stereotyped idiotypes may be in-volved in some HBV-associated monoclonallymphoproliferative disorders2,7 should befurther addressed.Conflict-of-interest disclosure: The authorsdeclare no competing financial interests. nREFERENCES1. Ren W, Ye X, Su H, et al. Genetic landscapeof hepatitis B virus–associated diffuse large B-celllymphoma. Blood. 2018;131(24):2670-2681.2. Deng L, Song Y, Young KH, et al. Hepatitis Bvirus-associated diffuse large B-cell lymphoma:unique clinical features, poor outcome, andhepatitis B surface antigen-driven origin.Oncotarget. 2015;6(28):25061-25073.3. Marcucci F, Mele A. Hepatitis viruses andnon-Hodgkin lymphoma: epidemiology,mechanisms of tumorigenesis, and therapeuticopportunities. Blood. 2011;117(6):1792-1798.4. Ng PP, Kuo CC, Wang S, et al. B-cell receptorsexpressed by lymphomas of hepatitis C virus(HCV)-infected patients rarely react with theviral proteins. Blood. 2014;123(10):1512-1515.5. Arcaini L, Besson C, Frigeni M, et al. Interferon-free antiviral treatment in B-cell lymphoprolif-erative disorders associated with hepatitis C virusinfection. Blood. 2016;128(21):2527-2532.6. Machida K, Cheng KT, Sung VM, et al. HepatitisC virus induces a mutator phenotype: en-hanced mutations of immunoglobulin andprotooncogenes. Proc Natl Acad Sci USA.2004;101(12):4262-4267.7. Visentini M, Pascolini S, Mitrevski M, et al.Hepatitis B virus causes mixed cryoglobulinaemiaby driving clonal expansion of innate B-cellsproducing a VH1-69-encoded antibody.Clin Exp Rheumatol. 2016;34(3 Suppl 97):S28-S32.8. XiongW, Lv R, Li H, et al. Prevalence of hepatitisB and hepatitis C viral infections in varioussubtypes of B-cell non-Hodgkin lymphoma:confirmation of the association with splenicmarginal zone lymphoma. Blood Cancer J.2017;7(3):e548.DOI 10.1182/blood-2018-05-847525© 2018 by The American Society of HematologyTRANSPLANTATIONComment on Holmqvist et al, page 2720Surviving childhoodcancer: a sobering storyMary Eapen | Medical College of WisconsinChildhood cancers account for <1% of all cancers diagnosed, which amounts to∼157 000 new cases annually. The table shows the common types of cancer andpercentage of occurrence; leukemia and brain tumor account for more thanhalf of all childhood cancers. In this issue of Blood, Holmqvist et al report on thelong-term survival of 362 survivors of childhood cancer whowere in continuousremission and alive 2 years after autologous hematopoietic cell transplantation.1Overall, there was a 23-fold increase inlate mortality compared with that in anage- and sex-matched general popula-tion. Recurrent primary disease was thepredominant cause of mortality in the first10 years after transplantation and the causefor half of all deaths in their cohort. The2 other major causes of late mortality werea second cancer and infection, each ac-counting for ;20% of deaths.In children, autologous transplantationsare reserved for high-risk solid tumors(as consolidation therapy) and for Hodgkinand non-Hodgkin lymphoma. Because thestudy population in Holmqvist et al datesback to 1980, about 25% of transplan-tations were for acute lymphoblastic ormyeloid leukemia. Because autologoustransplantations are no longer offered foracute leukemia in children, subset anal-yses that excluded childhood survivorsof acute leukemia were undertaken; theanalyses confirmed that the risks for latemortality were consistent with those ob-served for the whole cohort. Althoughmortality rates decline in those who sur-vive for more than 10 years, the numbersof patients are substantially fewer. Studiesthat include an adequate number of verylong-term survivors are needed to under-stand the risks of late mortality in thesesurvivors.A recent report on late mortality fromCanada observed that 25% of long-termsurvivors of autologous transplantationsuffered a later death (death occurring.2 years after transplantation).2 Yet thereare differences between the reports. InInfection/mutagenesisAntigenic stimulationHBVDLBCLAg-dependentBCR signaling clonal expansionAID-induced mutagenesis(BCL6, FOXO pathway)tonic BCR signalingType 2 mixedcryoglobulinemiaHBV might exploit 2 different mechanisms for causingeither indolent (mixed cryoglobulinemia) or highlymalignant (DLBCL) B-cell lymphoproliferative disor-ders. In the case of DLBCL, HBV infection of B cellsmay enhance overall mutagenesis (possibly throughAPOBEC enzymes) and alter B-cell–specific signalingpathways (possibly through AID). Among the latter,alterations in the FOXO pathway might result in lym-phomagenic tonic B-cell receptor signaling. DLBCLcells do not seem to express stereotyped idiotypesputatively recognizing HBV antigens. Conversely, inmixed cryoglobulinemia, continual antigenic stim-ulation by HBV may drive the clonal expansion ofB cells expressing specific stereotyped idiotypesthat regress upon suppression of infection by antiviraltherapy. There is no evidence suggesting the possi-bility of progression from mixed cryoglobulinemia toDLBCL.blood® 14 JUNE 2018 | VOLUME 131, NUMBER 24 2603For personal use only.on June 20, 2018. by guest  www.bloodjournal.orgFrom doi:10.1182/blood-2018-05-8475252018 131: 2602-2603  Marcella Visentini and Milvia Casato HBV messing with the B-cell genome leads to DLBCL http://www.bloodjournal.org/content/131/24/2602.full.htmlUpdated information and services can be found at: (2806 articles)Lymphoid Neoplasia     (5044 articles)Free Research Articles    Articles on similar topics can be found in the following Blood collectionshttp://www.bloodjournal.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at:http://www.bloodjournal.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at:http://www.bloodjournal.org/site/subscriptions/index.xhtmlInformation about subscriptions and ASH membership may be found online at:  Copyright 2011 by The American Society of Hematology; all rights reserved.of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American SocietyFor personal use only.on June 20, 2018. by guest  www.bloodjournal.orgFrom 

HBV messing with the B-cell genome leads to DLBCL

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HBV messing with the B-cell genome leads to DLBCL

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