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Aberrant Expression of Tetraspanin Molecules in B-Cell Chronic Lymphoproliferative Disorders and Its Correlation with Normal B-Cell Maturation

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Aberrant Expression of Tetraspanin Molecules in B-Cell Chronic Lymphoproliferative Disorders and Its Correlation with Normal B-Cell Maturation Leukemia (2005) 19, 1376–1383 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation S Barrena1,2, J Almeida1,2, M Yunta1,ALo´pez1,2, N Ferna´ndez-Mosteirı´n3, M Giralt3, M Romero4, L Perdiguer5, M Delgado1, A Orfao1,2 and PA Lazo1 1Instituto de Biologı´a Molecular y Celular del Ca´ncer, Centro de Investigacio´n del Ca´ncer, Consejo Superior de Investigaciones Cientı´ficas-Universidad de Salamanca, Salamanca, Spain; 2Servicio de Citometrı´a, Universidad de Salamanca and Hospital Universitario de Salamanca, Salamanca, Spain; 3Servicio de Hematologı´a, Hospital Universitario Miguel Servet, Zaragoza, Spain; 4Hematologı´a-hemoterapia, Hospital Universitario Rı´o Hortega, Valladolid, Spain; and 5Servicio de Hematologı´a, Hospital de Alcan˜iz, Teruel, Spain Tetraspanin proteins form signaling complexes between them On the cell surface, tetraspanin antigens are present either as and with other membrane proteins and modulate cell adhesion free molecules or through interaction with other proteins.25,26 and migration properties. The surface expression of several tetraspanin antigens (CD9, CD37, CD53, CD63, and CD81), and These interacting proteins include other tetraspanins, integri- F 22,27–30F their interacting proteins (CD19, CD21, and HLA-DR) were ns particularly those with the b1 subunit HLA class II 31–33 34,35 analyzed during normal B-cell maturation and compared to a moleculesFeg HLA DR -, CD19, the T-cell recep- group of 67 B-cell neoplasias. Three patterns of tetraspanin tor36,37 and several other members of the immunoglobulin expression were identified in normal B cells. The first superfamily.38 As an example, CD81 binds to a CD19/CD21 þ corresponded to bone marrow CD10 B-cell precursors (BCP) complex on B-cells,39 as well as to CD9 and CD82.35 The which showed high expression of CD81 and CD9, low reactivity for CD53 and negativity for CD37. CD10À B-lymphocytes diversity in the composition of tetraspanins, and those proteins showed downregulation of CD9/CD81 and upregulation of interacting with the tetraspanin-containing membrane com- CD53/CD37. Plasma cells showed re-expressed CD9 and down- plexes allows for a larger plasticity of their signaling proper- regulated CD37. Hierarchical clustering analysis of flow cyto- ties.15,23,24 Overall, it is likely that the pattern of expression of metry immunophenotypic data showed a good correlation tetraspanin proteins is a major determining factor in the specific between the tumor differentiation stage and the pattern of adhesion and homing properties of a cell,40 and that changes in tetraspanin expression, with all analyzed individual samples classified into three major groups, independently of their this profile will be followed by a redistribution of the cell within normal or neoplastic origin. Despite this, neoplastic B-cells the organism in terms of its developmental stage or functional frequently showed aberrantly high/low expression of the state. As a result of the complex pattern of tetraspanin gene different markers analyzed. Interestingly, in B-cell chronic expression, it is very likely that the adhesion and migration lymphocytic leukemia, abnormal expression of CD53 and CD9 properties of tumor cells are also influenced by the alteration in were associated with different patterns of disease infiltration, the composition of cell-specific tetraspanin protein complexes. which would support the role of these molecules on modulating Abnormal levels of tetraspanin antigens have been identified adhesion and migration of neoplastic B cells. 41,42 Leukemia (2005) 19, 1376–1383. doi:10.1038/sj.leu.2403822; in many different types of carcinomas. In general, low published online 2 June 2005 expression of some individual molecules has been related to a poor prognosis. Accordingly, low levels of CD63 in melano- Keywords: tetraspanin; B cells; B-cell neoplasias; B-cell mas43 as well as in colon carcinomas42 indicated a higher maturation; immunophenotype; flow cytometry metastatic potential. Additional correlations between abnor- mally low levels of tetraspanin molecules and poor prognosis have been reported for CD9 in the lung,9 oral,44 cervical45 and 8 12,46,47 48 Introduction breast carcinomas and for CD82 in the prostate, breast and lung cancer.49 Interestingly, re-expression of CD950 and 12 Tetraspanin proteins are a group of structurally related CD82 in the tumor cells increases their adhesion and membrane proteins involved in cell adhesion1–7 motility8–16 subsequently reduces their motility. Regarding CD53, its and apoptosis;17 the exact mechanisms through which they reduced expression in normal cells is associated with a syndrome very similar to leukocyte adhesion defects, character- modulate these processes remains unknown. They have four 51 common transmembrane domains with four, six or eight ized by recurrent infections. cysteine residues and a CCG motif in the largest extracellular In the present study, we have quantitatively analyzed the loop.18,19 In all, 25 members have been identified so far. distribution and the pattern of expression of several tetraspanin Although the expression of some of these molecules is limited antigens in normal and neoplastic human B cells. Our results almost exclusively to lymphoid or myeloid cells (eg CD37), show a high frequency of aberrant expression of tetraspanin most tetraspanin are widely expressed in many non,hemato- molecules in tumor B cells. Despite this, the overall pattern of poietic cell types (eg CD9, CD63 and CD81).20,21 Mammalian expression of these proteins during normal B-cell maturation cells simultaneously express several tetraspanin antigens, which correlated with the stage of maturation arrest in B-cell might form specific complexes on the plasma mem- neoplasias, which could be of help for diagnostic purposes. brane.15,18,22–24 Materials and methods Correspondence: Dr PA Lazo, Centro de Investigacio´n del Ca´ncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Fax: þ 34 923 294 795; Controls and patients E-mail: [email protected] Received 4 February 2005; accepted 18 April 2005; published online Analysis of the expression of tetraspanin molecules and other 2 June 2005 functionally related surface proteins along the normal B-cell Tetraspanin antigen switch in B-cell neoplasias S Barrena et al 1377 differentiation was performed on a total of 17 normal samples performed. In the first step, information was stored on a obtained from subjects without any known disease and with minimum of 3 Â 104 nucleated cells corresponding to the whole normal blood cell counts: six bone marrow (BM) and nine sample cellularity. In the second step, acquisition through an peripheral blood (PB) samples obtained from an identical electronic ‘live gate’ was carried out; in normal BM and PB number of healthy adult volunteers and two reactive lymph samples, as well as in samples from immature and mature B-cell node samples. In turn, normal residual plasma cells (PC) were malignancies, the electronic ‘live gate’ was drawn on the analyzed in three BM samples from an identical number of CD19 þ region in which B-cells are located, while in BM patients with monoclonal gammopathy of undetermined sig- samples from normal individuals, MGUS and MM patients a nificance (MGUS). ‘live gate’ drawn on the CD38 þþþ region was applied in order In addition, a total of 25 BM, 41 PB and one lymph to specifically select PC. In this second step, information on a node sample from a total of 67 newly diagnosed untreated minimum of 104 CD19 þ B-cells or CD38 þþþ, PC was stored. patients with clonal B-cell malignancies, were studied. For data analysis, the Paint-A-Gate PRO software (BDB) was Diagnosis of the different B-cell malignancies was based on used. Expression of tetraspanin molecules was assessed in the clinical, morphologic, immunophenotypic and molecular cri- following subpopulations of CD19 þ B-cells and/or CD38 þþþ teria, according to the WHO classification.52 Patients PC: BM CD34 þ /CD19 þ B-cell precursors (BCP), BM CD34À/ were distributed as follows: CD34 þ precursor B acute CD19 þ BCP, PB CD19 þ mature B lymphocytes, lymph node lymphoblastic leukemia (B-ALL), eight patients FBII: seven, CD19 þ B cells and BM CD38 þþþ PC. For each antigen one being t(bcr/abl) þ , BIII: 1_;53 CD34À precursor B-ALL, analyzed, the intensity of expression was evaluated by the mean four patientsFall BIII (one with t(8;14) þ and another fluorescence intensity (MFI), observed for the specific cell with t(12;21) þ );53 B-cell chronic lymphocytic leukemia (B- population under analysis and expressed either as absolute CLL), 28 patientsF25 typical (typ) and three atypical (atyp) MFI values (arbitrary relative linear units scaled from 0 to 104)or B-CLLÀ; prolymphocytic leukemia (PLL), one patient; hairy as a percentage of the maximum MFI observed for that antigen cell leukemia (HCL), two; mantle cell lymphoma (MCL), in normal B cells. threeFall being t(11;14) þ ; splenic marginal zone lymphoma (SMZL), one; MALT lymphoma, five cases; follicular lymphoma (FL), two patientsFboth being t(14;18) þ ; bcl6 þ diffuse large Statistical methods and hierarchical clustering analysis B-cell lymphoma (DLBCL), one patient; Burkitt‘s lymphoma, two patientsFone being t(8;14) þ ; multiple myeloma (MM), five Mean values and their standard deviation, as well as median, patients; and MGUS, five cases. Samples from both the patients range, 25 and 75th percentiles and 95% confidence intervals and the controls were obtained after informed consent, were calculated for each variable. Statistical analyses were according to the Ethics Committee of the University Hospital performed with the SPSS 11.0 software program (SPSS Inc., of Salamanca (Salamanca, Spain). Chicago, IL, USA). For the evaluation of the statistical significance of the differences observed between groups, the Mann–Whitney U-test was used.
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