RESUMEN
Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Dioxigenasas/metabolismo , Células Asesinas Naturales/metabolismo , Linfoma de Células T/metabolismo , Mutación , Proteínas de Neoplasias/metabolismo , Receptores KIR/metabolismo , Factor de Transcripción STAT3/metabolismo , Anciano , Enfermedad Crónica , Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Femenino , Células Madre Hematopoyéticas/metabolismo , Humanos , Linfoma de Células T/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Receptores KIR/genética , Factor de Transcripción STAT3/genéticaRESUMEN
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
PURPOSE: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia. FINDINGS: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. CONCLUSIONS: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginasa/uso terapéutico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Anciano , Antibacterianos/uso terapéutico , Antifúngicos/uso terapéutico , Asparagina/metabolismo , Portadores de Fármacos , Composición de Medicamentos , Eritrocitos/química , Eritrocitos/citología , Femenino , Infecciones por Bacterias Gramnegativas/complicaciones , Infecciones por Bacterias Gramnegativas/mortalidad , Infecciones por Bacterias Gramnegativas/patología , Infecciones por Bacterias Grampositivas/complicaciones , Infecciones por Bacterias Grampositivas/mortalidad , Infecciones por Bacterias Grampositivas/patología , Humanos , Masculino , Persona de Mediana Edad , Micosis/complicaciones , Micosis/mortalidad , Micosis/patología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
The management of hematologic malignancies has entered a new era in which minimal residual disease (MRD) monitoring plays a pivotal role. Well-established molecular targets such as PML::RARA, CBFB::MYH11 or RUNX1::RUNX1T1 are conventionally tracked by quantitative reverse-transcription PCR. Recently, a broader landscape of fusion transcripts has been unveiled through transcriptomic analysis. These newly discovered fusion transcripts may emerge as novel molecular markers for MRD quantification. In this study, we compared a targeted RNA-seq approach (FusionPlex) with a whole transcriptomic strategy (Advanta RNA-seq XT) for fusion detection in a training set of 21 samples. We evidenced a concordance of 100% for the detection of known fusions, and showed a good correlation for gene expression quantification between the two techniques (Spearman r=0.77). Additionally, we prospectively evaluated the identification of fusions by targeted RNA-seq in a real-life series of 126 patients with hematological malignancy. At least one fusion transcript was detected for 60 patients (48%). We designed tailored digital PCR assays for 11 rare fusions, and validated this technique for MRD quantification with a limit of detection below 0.01%. The combination of RNA-seq and tailored digital PCR may become a new standard for MRD evaluation in patients lacking conventional molecular targets.
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Reordenamiento Génico , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Glicoproteína Asociada a Mielina/inmunología , Factor 88 de Diferenciación Mieloide/genética , Paraproteinemias/genética , Enfermedades del Sistema Nervioso Periférico/genética , Receptores CXCR4/genética , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina M , Masculino , Persona de Mediana Edad , Mutación , Paraproteinemias/patología , Enfermedades del Sistema Nervioso Periférico/patología , PronósticoAsunto(s)
Antineoplásicos/uso terapéutico , Sustitución de Medicamentos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2-detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10-4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.
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Linfoma Folicular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Lenalidomida/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Pronóstico , Rituximab/uso terapéuticoRESUMEN
INTRODUCTION: The monitoring of minimal residual disease (MRD) approach in patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) allows an early detection of residual clones inducing relapses and therefore appropriate therapy strategy. The molecular markers may identify and quantify the residual blasts in B-ALL with normal cytology. In this study, we aimed to use combined IKZF1, IGH and IGK immunoglobulin genes for diagnosis and MRD monitoring in B-ALL sample using MLPA, multiplex PCR and real-time quantitative PCR. MATERIAL: We showed that multiplex PCR and MLPA are necessary and complementary to detect IKZF1 deletions. RESULTS: We have identified at the diagnosis clonal IGH rearrangement (VH3-JH5) and IKZF1 deletion (Δ4-7), which we have used it for MRD evaluation after induction chemotherapy. Despite the absence of chromosome abnormality, the patient may be classified in high-risk group with a relapse rate of residual blasts>10-4 and sensitivity up to 10-5. This molecular approach enabled the patient's stratification, which was overlooked by classical methods. CONCLUSION: The combined IKZF1 and immunoglobulin genes will be used as appropriate molecular tools for diagnosis and MRD assessment of B-lineage leukemias and introduced as a routine tests in Tunisian clinical laboratories. They will be useful to stratify patients into risk groups leading to better treatment strategy.
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Eliminación de Gen , Genes de Inmunoglobulinas , Factor de Transcripción Ikaros/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Marcadores Genéticos , Humanos , Reacción en Cadena de la Polimerasa Multiplex , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologíaAsunto(s)
Leucemia Linfocítica Crónica de Células B , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , PronósticoRESUMEN
DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin-1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC-induced apoptosis is associated with lymphomagenesis. In human diffuse large B-cell lymphoma (DLBCL), an imbalance of the netrin-1/DCC ratio suggests a loss of DCC-induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up-regulation of netrin-1 in activated B-cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin-1 interfering antibody, we demonstrate both in vitro and in vivo that netrin-1 acts as a survival factor for ABC-DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin-1/DCC interaction could represent a promising therapeutic strategy in netrin-1-positive DLBCL and MCL.
Asunto(s)
Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Factores de Crecimiento Nervioso/antagonistas & inhibidores , Receptores de Superficie Celular/metabolismo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/metabolismo , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Receptor DCC , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Ratones , Ratones Transgénicos , Netrina-1 , Unión ProteicaRESUMEN
Chromosomal rearrangements involving the MLL gene at band 11q23 are the most common genetic alteration encountered in infant acute myeloid leukemia. Reciprocal translocation represents the most frequent form of MLL rearrangement. Currently, more than 60 partner genes have been identified. We report here a case of de novo acute myeloid leukemia with a t(11;22)(q23;q11) in a 23-month-old child. Fluorescence in situ hybridization study revealed that the 3'MLL segment was translocated onto the derivative chromosome 22 and the breakpoint on chromosome 22 was located in or near the SEPT5 gene at 22q11.21. Long distance inverse-polymerase chain reaction was used to identify precisely the MLL partner gene and confirmed the MLL-SEPT5 fusion transcript. Involvement of the SEPT5 gene in MLL rearrangement occurs very rarely. Clinical, cytogenetic and molecular features of acute myeloid leukemia with a MLL-SEPT5 fusion gene are reviewed.
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Cromosomas Humanos Par 11 , Cromosomas Humanos Par 22 , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Transcripción Genética , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuencia de Bases , Bandeo Cromosómico , Puntos de Rotura del Cromosoma , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Datos de Secuencia Molecular , Inducción de RemisiónAsunto(s)
Heterogeneidad Genética , Mutación , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/genética , Adolescente , Adulto , Biomarcadores de Tumor , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Cariotipificación , Masculino , Persona de Mediana Edad , Pronóstico , Sarcoma Mieloide/mortalidad , Adulto JovenRESUMEN
Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL4-inducible gene and is highly expressed in primary mediastinal B-cell lymphomas. We established stable HEK293 clones expressing human and mouse IL4I1 to examine their biochemical properties and function. Both proteins were secreted into the culture medium, and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B-cell line, MedB-1. We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigen-presenting cell/T-lymphocyte cross-talk. Indeed, hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells. In contrast, memory T cells were more strongly affected by hIL4I1 and its catabolite H(2)O(2) than naive T cells. hIL4I1 inhibitory effect was dependent on enzymatic activity and H(2)O(2) production and associated with a transient down-regulation of TCRzeta expression. Altogether these data suggest IL4I1 as a new immunomodulatory enzyme produced by DCs.
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Aminoácido Oxidorreductasas/inmunología , Proliferación Celular , Células Dendríticas/química , L-Aminoácido Oxidasa/inmunología , Linfocitos T/citología , Aminoácido Oxidorreductasas/biosíntesis , Aminoácido Oxidorreductasas/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Humanos , Peróxido de Hidrógeno/metabolismo , Inmunohistoquímica , L-Aminoácido Oxidasa/biosíntesis , L-Aminoácido Oxidasa/metabolismo , Linfoma de Células B/patología , Macrófagos/química , Ratones , Células Mieloides/químicaRESUMEN
Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the functional state of the signal transducer and activator of transcription 6 (STAT6), mediating IL-4/IL-13 transcriptional effects. Constitutive STAT6 phosphorylation and DNA-binding activity were detected in PMBL cell lines but not DLBCL cell lines. Moreover, immunohistochemical analysis revealed nuclear phosphorylated STAT6 (P-STAT6) in 8 of 11 PMBL, compared with 1 of 10 DLBCL primary tumors (P =.01). IL-4 and IL-13 transcripts were absent in PMBL cell lines and expressed at low levels in tumors, indicating that, contrary to classical Hodgkin lymphoma (cHL), STAT6 activation is not due to an autocrine IL-4/IL-13 secretion. We demonstrated an amplification of the JAK2 gene in 2 of 6 PMBL cases, and showed higher JAK2 mRNA levels in PMBL compared with DLBCL (P =.005). The Janus kinase 2 (JAK2) was constitutively phosphorylated in the PMBL MedB1 cell line. MedB1 treatment with JAK2 inhibitor AG490 partially decreased STAT6 phosphorylation, suggesting that JAK2 is partially involved in STAT6 activation in these cells. Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas.
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Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Neoplasias del Mediastino/metabolismo , Proteínas Proto-Oncogénicas , Transactivadores/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-13/genética , Interleucina-4/genética , Janus Quinasa 2 , Linfoma de Células B/fisiopatología , Linfoma de Células B Grandes Difuso/fisiopatología , Neoplasias del Mediastino/fisiopatología , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Factor de Transcripción STAT6RESUMEN
The MAL mRNA was initially identified during T-cell development and was later found in myelin-forming cells and certain polarized epithelial cell lines. It encodes a proteolipid believed to participate in membrane microdomains stabilization, transport machinery and signal transduction. Using a differential display reverse-transcription approach, we identified MAL as a distinct molecular marker of primary mediastinal large B-cell lymphoma compared with nonmediastinal diffuse large B-cell lymphomas. In the present study, we used immunohistochemistry to extend MAL expression analysis to normal lymphoid tissues; to 185 lymphomas representing most B, T, and Hodgkin lymphoma entities; and to the primary mediastinal large B-cell lymphoma derived B-cell line MedB-1. In addition, B and T cells from peripheral blood, tonsil, and spleen were analyzed by flow cytometry. Our results show that MAL is highly expressed in thymocytes, in a large percentage of peripheral CD4 T cells, and in a lower proportion of CD8 peripheral T cells. In the normal B-cell compartment, MAL expression appears to be restricted to a minor subpopulation of thymic medullary B cells and to occasional mature plasma cells located in the interfollicular areas of tonsil and lymph nodes. Among B-cell lymphomas (n = 110), MAL expression in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas. The MedB-1 B-cell line was also MAL positive. Among T-cell neoplasms, MAL was highly expressed in lymphoblastic tumors (5/6), whereas mature T-cell lymphomas were essentially MAL negative (27/28). Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with mediastinal involvement showed MAL-positive Reed Sternberg cells. In conclusion, this study further supports thymic B cells as the putative normal counterpart of primary mediastinal large B-cell lymphomas and supports MAL as a distinct molecular marker of this lymphoma subtype among diffuse large B-cell lymphomas.
Asunto(s)
Linfoma de Células B/patología , Neoplasias del Mediastino/patología , Proteínas de Transporte de Membrana , Proteínas de la Mielina , Proteolípidos/biosíntesis , Antígenos CD/análisis , Biomarcadores de Tumor/análisis , Antígenos CD79 , Citometría de Flujo , Humanos , Inmunohistoquímica/métodos , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Linfocitos/química , Linfoma de Células B/metabolismo , Neoplasias del Mediastino/metabolismo , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito , Tonsila Palatina/química , Tonsila Palatina/patología , Receptores de Antígenos de Linfocitos B/análisis , Bazo/química , Bazo/patología , Timo/química , Timo/patologíaRESUMEN
The molecular markers that distinguish primary mediastinal large B-cell lymphoma (PMBL) from nonmediastinal diffuse large B-cell lymphomas (NM-DLBLs) remain to be identified. Using cDNA representational difference analysis to compare PMBL and NM-DLBL transcripts, we isolated a cDNA fragment homologous to the mouse B-cell interleukin 4 (IL-4)-inducible gene FIG1 (interleukin 4-induced gene 1) transcript. The human FIG1 mRNA encodes a 567 amino acid protein that comprises a signal peptide and a large flavin-binding amino oxidase domain, and shares significant homology with secreted apoptosis-inducing L-amino acid oxidases. Northern blot studies showed that FIG1 mRNA expression is mainly restricted to lymphoid tissues. It is expressed at low levels in thymus, spleen, tonsils, and reactive lymph nodes, and is highly up-regulated in IL-4+CD40-activated tonsillar B cells. Interestingly, in human B-cell lines, FIG1 mRNA expression appeared restricted to the PMBL-derived MedB-1 and Karpas 1106 cell lines. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that all but one PMBL (16/17) displayed high FIG1 mRNA levels, whereas most NM-DLBLs (12/18) and all low-grade B-cell lymphomas tested (8/8) exhibited low FIG1 mRNA levels. The difference between PMBLs and NM-DLBLs was statistically significant (Fisher test; P =.0003). Southern blot studies did not show rearrangement of the FIG1 gene. FIG1 gene expression might be due to a constitutive activation of a cytokine signaling pathway in PMBL.