A. Carbone

A. Gloghini

D. Gasparotto

GRAGNANI, LAURA

M. Boiocchi

M. C. Mazzarino

M. Libra

P. M. Navolanic

S. De Vita

V. De Re

ZIGNEGO, ANNA LINDA

English

Archivio della Ricerca - Università di Pisa

Letters to the Editorhaematologica 2004; 89(7):July 2004 873occurrence of the c-kit Asp816Val activating mutation in T cells,B cells, and myelomonocytic cells in patients with mastocytosis.Exp Hematol 2000;28:140-7.6. Afonja O, Amorosi E, Ashman L, Takeshita K. Multilineage involve-ment and erythropoietin independent erythroid progenitor cellsin a patient with systemic mastocytosis. Ann Hematol 1998;77:183-6.7. Sotlar K, Fridrich C, Mall A, Jaussi R, Bultmann B, Valent P, et al.Detection of c-kit point mutation Asp-816→Val in microdissect-ed pooled single mast cells and leukemic cells in a patient withsystemic mastocytosis and concomitant chronic myelomonocyt-ic leukemia. Leuk Res 2002;26:979-84.8. Pardanani A, Reeder T, Li CY, Tefferi A. Eosinophils are derivedfrom the neoplastic clone in patients with systemic mastocytosisand eosinophilia. Leuk Res 2003;27:883-5.9. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, etal. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1genes as a therapeutic target of imatinib in idiopathic hypere-osinophilic syndrome. N Engl J Med 2003;348:1201-14.10. Reeder TL, Bailey RJ, Dewald GW, Tefferi A. Both B and T lym-phocytes may be clonally involved in myelofibrosis with myeloidmetaplasia. Blood 2003;101:1981-3.Malignant LymphomasDetection of bcl-2 rearrangement in mucosa-associatedlymphoid tissue lymphomas from patients with hepatitisC virus infectionIt has been shown that t(14;18)(q32;q21) involvingfusion of IGH with MALT1 occurs frequently in mucosa-associated lymphoid tissue (MALT) lymphomas. Resultsof the present study indicate that the classical form oft(14;18)(q32;q21) involving fusion of IGH with bcl-2can be detectable in a subset of MALT lymphomas inpatients with hepatitis C virus (HCV) infection. haematologica 2003; 88:873-874(http://www.haematologica.org/2004/7/873)Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) compriseapproximately 8% of non-Hodgkin’s lymphomas (NHL) andare among the 6 most common forms of NHL. MALT lym-phomas usually result from chronic stimulation of B-cells bypersistent infection or autoimmune processes.1 Among thegenetic abnormalities associated with MALT lymphomas,t(11;18)(q21;q21) is the most common. This translocationfuses apoptosis inhibitor-2 (API2) with MALT lymphoma-associated translocation gene-1 (MALT1).1 However, Streubelet al. showed that t(14;18)(q32;q21) involving fusion of theimmunoglobulin heavy chain gene (IGH) with MALT1 alsooccurs in MALT lymphomas.2 This finding was supported byrecent reports from Sanchez-Izquierdo et al. and MurgaPenas et al.3,4 The translocation described by these 3 groupswas detected most frequently in MALT lymphomas of theconjunctiva, liver, skin, parotid gland, and salivary gland.Interestingly, all of these anatomical sites are susceptible tohepatitis C virus (HCV) infection.5Chronic antigenic stimulation of B-cells resulting fromHCV infection has been suggested to contribute to the devel-opment of lymphoproliferative disorders.6 Previous studieshave also suggested a role for the bcl-2 rearrangement dur-ing development of lymphoproliferative disorders amongHCV-infected individuals.7 However, the incidence of theclassical form of t(14;18)(q32;q21) involving fusion of IGHwith bcl-2 has not been investigated in MALT lymphomapatients. In the present study, MALT lymphoma tissue from 11HCV-infected and 9 HCV-negative patients was analyzed forthe presence of this translocation (Table 1). DNA isolatedfrom MALT lymphoma biopsy specimens was analyzed for thepresence of bcl-2 rearrangement at the major (MBR) andminor breakpoint regions (mcr) by polymerase chain reaction(PCR) as previously described.8 The MALT lymphoma biopsyspecimens were collected from the primary site of disease.Rearrangement of bcl-2 was detected in 5 of 20 (25%)MALT lymphoma biopsy specimens after both the first andsecond rounds of amplification. Control experiments wereperformed to verify that the methods used to test for bcl-2rearrangement were reliable. Tumor biopsy specimens from15 of 15 HCV-negative follicular lymphoma (FL) patientswere positive for bcl-2 rearrangement. Of these transloca-tions, 13 occurred at the MBR and 2 occurred at the mcr. Incontrast, bcl-2 rearrangement was not detected in peripher-al blood mononuclear cell from 50 healthy HCV-negativedonors. These positive and negative control experimentsdemonstrate that the methods used to test for bcl-2rearrangement reliably detected the genetic abnormalitywithout yielding false positive results. MALT lymphoma biopsy specimens were also analyzed forexpression of Bcl-2, Bcl-6, and CD10 by immunohistochem-istry. All MALT lymphoma biopsy specimens tested were neg-ative for both Bcl-6 and CD10 expression, which excludes thepossibility that these tumors were of follicular origin. Bcl-2expression was analyzed in MALT lymphoma biopsy speci-mens from 3 of 5 patients positive for the bcl-2 rearrange-ment and from 12 of 15 patients negative for the bcl-2rearrangement. Bcl-2 expression was detected in 3 of 3patients positive for the bcl-2 rearrangement, a result con-sistent with those of previous studies correlating Bcl-2expression with the bcl-2 rearrangement.9 Bcl-2 wasexpressed in 8 of 12 MALT lymphoma biopsy specimens neg-Table 1. Clinical characteristics and bcl-2 rearrangementstatus of the MALT lymphoma patients studied.Patient Age/ Sites HCV MC bcl-2 Sex of Disease Status Rearr.1 65/F Stomach, BM + + +2 66/F Skin + + −3 59/M Liver, BM + + +4 66/F Stomach + + −5 55/F Salivary gland, BM + + −6 69/F Salivary gland, BM + − +7 51/F Skin, BM + − −8 79/M Salivary gland, stomach + − −9 72/F Stomach + − +10 57/F Salivary gland, BM + − −11 60/F Lung, BM + − −12 38/M Ocular adnexa, BM − − −13 70/F Stomach, BM − − +14 69/F Stomach, spleen − − −15 64/M Fatty renal capsule, BM − − −16 61/F Stomach, BM − − −17 65/F Stomach, BM − − −18 60/F Stomach, spleen, BM − − −19 71/M Stomach, BM − − −20 67/M Stomach, BM − − −Rearr.: rearrangement; BM: bone marrow; F: female; M: male; MC: type II mixedcryoglobulinemia syndrome. Letters to the Editorhaematologica 2004; 89(7):July 2004874ative for the bcl-2 rearrangement. It is possible that Bcl-2expression in these MALT lymphomas is driven by mecha-nisms other than the bcl-2 rearrangement, as has beenreported elsewhere.10,11Rearrangement of bcl-2 has been proposed to be involvedin the multistep mechanism of lymphomagenesis. IncreasedBcl-2 expression promotes clonal expansion of B cells by pre-venting apoptosis. Previous studies have suggested that thebcl-2 rearrangement contributes to the pathogenesis of lym-phoproliferative disorders associated with HCV infection.7 Inagreement with this possibility, the results of the presentstudy indicate that the bcl-2 rearrangement can be detectedin a subset of MALT lymphomas from HCV-infected patients(Figure 1). It is important to point out that 15 of the 20 MALTlymphoma patients studied had bone marrow involvement.Therefore, it would also be of interest to investigate the fre-quency of bcl-2 rearrangement among MALT lymphomapatients with an earlier stage of disease. Additional studiesare required to clarify the relationship between bcl-2rearrangement and MALT lymphoma development in boththe presence and absence of HCV infection.An interaction between genetic influences and environ-mental stimuli during lymphomagenesis has been suggestedpreviously.9 This interaction is illustrated by a patient whodeveloped follicular lymphoma 2 years after being diagnosedwith MALT lymphoma. Rearrangement of bcl-2 was presentin both the follicular and MALT lymphomas and VDJrearrangement analysis indicated that both lymphomas werederived from the same B-cell clone. It was postulated thatthe follicular lymphoma in this patient may have developedas a result of co-operation between the presence of bcl-2rearrangement and B-cell exposure to the germinal centerenvironment. HCV infection may serve as an environmentalstimulus that supports development of MALT lymphomasharboring the bcl-2 rearrangement.Massimo Libra,*§ Valli De Re,* Annunziata Gloghini,°Daniela Gasparotto,* Laura Gragnani,# Patrick M. Navolanic,@§Salvatore De Vita,^ Maria Clorinda Mazzarino,§ Anna LindaZignego,# Antonino Carbone,° Mauro Boiocchi**Division of Experimental Oncology, °Division of Pathology,Centro di Riferimento Oncologico, Aviano, Pordenone, Italy;#Department of Internal Medicine, University of Florence, Italy;@Department of Microbiology and Immunology, Brody School ofMedicine at East Carolina University, Greenville, NC, USA;ˆDivision of Rheumatology, DPMSC, University of Udine, Italy;§Department of Biomedical Sciences, University of Catania, ItalyKey words: MALT lymphoma, bcl-2 rearrangement, t(14;18),hepatitis C virus.Funding: This work was funded in part by the Italian Associationfor Research on Cancer (AIRC). The authors thank Mrs. LuiginaMei for editorial assistance.Correspondence: Dr. Mauro Boiocchi, Division of ExperimentalOncology 1, Centro di Riferimento Oncologico, Via PedemontanaOccidentale 12, 3301 Aviano (PN). Phone: international+39.0434.659300. Fax: international +39.0434.659659.E-mail: mboiocchi@cro.it/os1@cro.itReferences1. Isaacson PG. Extranodal marginal zone B-cell lymphoma ofmucosa-associated lymphoid tissue (MALT lymphoma). In: Jaffe ES,Harris NL, Stein H, Vardiman JW, editors. World HealthOrganization Classification of Tumours. Pathology and Genetics:Tumours of Haemopoietic and Lymphoid Tissues. Lyon, France:IARC Press: 2001.2. Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, etal. t(14;18)(q32;q21) involving IGH and MALT1 is a frequent chro-mosomal aberration in MALT lymphoma. Blood 2003; 101:2335-9.3. Sanchez-Izquierdo D, Buchonnet G, Siebert R, Gascoyne RD,Climent J, Karran L, et al. MALT1 is deregulated by both chromo-somal translocation and amplification in B-cell non-Hodgkin lym-phoma. Blood 2003;101:4539-46.4. Murga Penas EM, Hinz K, Röser K, Copie-Bergman C, Wlodarska I,Marynen P, et al. Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involvingMLT/MALT1 in MALT lymphomas. Leukemia 2003; 17:2225-9.5. De Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, CrovattoM, et al. Characterization of overt B-cell lymphomas in patientswith hepatitis C virus infection. Blood 1997;90:776-82.6. De Re V, De Vita S, Marzotto A, Rupolo M, Gloghini A, Pivetta B, etal. Sequence analysis of the immunoglobulin antigen receptor ofhepatitis C virus-associated non-Hodgkin lymphomas suggeststhat the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia.Blood 2000;96:3578-84.7. Zignego AL, Giannelli F, Marrocchi ME, Mazzocca A, Ferri C,Giannini C, et al. t(14;18) translocation in chronic hepatitis C virusinfection. Hepatology 2000;31:474-9.8. Libra M, De Re V, De Vita S, Gasparotto D, Gloghini A, Rupolo M, etal. Low frequency of bcl-2 rearrangement in HCV-associated non-Hodgkin’s lymphoma tissue. Leukemia 2003;17:1433-6.9. Aiello A, Du MQ, Diss TC, Peng HZ, Pezzella F, Papini D, et al.Simultaneous phenotypically distinct but clonally identicalmucosa-associated lymphoid tissue and follicular lymphoma in apatient with Sjögren's syndrome. Blood 1999;94:2247-51.10. Pan L, Diss TC, Cunningham D, Isaacson PG. The bcl-2 gene in pri-mary B cell lymphoma of mucosa-associated lymphoid tissue(MALT). Am J Pathol 1989;135:7-11.11. Casato M, Mecucci C, Agnello V, Fiorilli M, Knight GB, Matteucci C,et al. Regression of lymphoproliferative disorder after treatmentfor hepatitis C virus infection in a patient with partial trisomy 3,Bcl-2 overexpression, and type II cryoglobulinemia. Blood2002;99:2259-61.Figure 1. DNA sequencesat the IGH/bcl-2 break-point of PCR productsamplified from MALTlymphoma biopsy speci-mens from all 4 HCV-infected patients who hadthe bcl-2 rearrangement.Nucleotide numberingcorresponds to that ofGenbank accession num-bers M14745 andM25625 for bcl-2 and theJH gene segment of IGH,respectively.N-segment 1481 Jhbcl-2 3170bcl-2 3098bcl-2 3138bcl-2 31121480 Jh1475 Jh1482 JhN-segmentN-segmentN-segmentPatient 1Patient 3Patient 6Patient 9 

Detection of bcl-2 rearrangement in mucosa-associated lymphoid tissue lymphomas from patients with hepatitis C virus infection

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Detection of bcl-2 rearrangement in mucosa-associated lymphoid tissue lymphomas from patients with hepatitis C virus infection

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