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Izidore S Lossos

Publications and source records attributed to Izidore S Lossos.

At least 19 recordsLinked to original sources
PubMed2007

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-alpha) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 10; 60%) more often than did sensitive variants (1 of 9; 11%). This finding was independent of the disease form. Elevated expression of the putative c-Rel target, interferon regulatory factor-4 (IRF-4), was observed in 10 (91%) of 11 nonresponders and in all tested patients with c-Rel+ tumors and occurred in the absence of the HTLV-1 oncoprotein Tax. In contrast, tumors in complete responders did not express c-Rel or IRF-4. Gene rearrangement studies demonstrated the persistence of circulating T-cell clones in long-term survivors maintained on antiviral therapy. The expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with antiviral resistance. These molecular features may help guide treatment. AZT and IFN-alpha is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely.

Adult↗
PubMed2007

T-cell protein tyrosine phosphatase, distinctively expressed in activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6.

Diffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC- versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.

Catalytic Domain↗
PubMed2006

The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas.

We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Expression of the human germinal center-associated lymphoma (HGAL) protein identifies a subset of classic Hodgkin lymphoma of germinal center derivation and improved survival.

The human germinal-center-associated lymphoma (HGAL) gene and its cognate protein are expressed in a germinal center (GC)-specific manner. Its expression in classic Hodgkin lymphoma (cHL) prompted us to address whether HGAL expression could distinguish biologically distinct subgroups of cHL. Tissue microarrays from 145 patients treated with curative intent showed HGAL staining in 75% and was closely correlated with MUM1/IRF4 (92%) expression. BCL6 (26%), CD10 (0%), BCL2 (31%), Blimp1 (0.02%), and Epstein-Barr virus (EBV) (20%) showed no specific correlation; neither did phospho-STAT6, a key mediator of IL-4 and IL-13 signaling that induces HGAL and is implicated in cHL pathogenesis. In our study cohort, the 5-year overall survival (OS) correlated with young age (less than 45 years, P < .001), low stage (stage I and II, P = .04), and low International Prognostic Score (P = .002). In univariate analysis, HGAL expression was associated with improved OS (P = .01) and failure-free survival (FFS) (P = .05) but was not independent of other factors in multivariate analysis of OS or FFS. The expression of the GC-specific marker HGAL in a subset of cHL suggests that these cHLs retain characteristics of GC-derived lymphomas. The association with improved OS in univariate but not multivariate analysis suggests that HGAL expression is related to known clinical parameters of improved survival.

Adult↗
PubMed2006

Prognostic biomarkers in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and response to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI still exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression led to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independently of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and the development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent advances in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.

Biomarkers, Tumor↗
PubMed2005

Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci.

Non-Hodgkin lymphomas are among the most common primary tumors occurring in the ocular adnexa. Herein, we present a 14-year single-institution experience in 62 patients with primary ocular adnexal lymphomas (OALs). Association with Chlamydia psittaci infection is examined in 57 tumor specimens. Extranodal marginal zone lymphoma (EMZL) was the most frequent histologic subtype (89%). The majority of patients with EMZL (84%) presented with stage E-extranodal (IE), however only 16% had an advanced stage. All stage IE patients were treated with local radiotherapy, whereas patients with disseminated disease received systemic therapy with or without local irradiation. All but 1 patient with EMZL achieved complete remission (CR). During a median follow-up of 52 months (range, 3-153 months), the estimated 5-year overall survival (OS) and freedom from progression (FFP) were 96% and 79%, respectively. During the follow-up, 22% of patients relapsed, mainly in extranodal sites, and 4% transformed to diffuse large B-cell lymphoma. None of the patients exhibited local orbital failure in the radiation field. None of the OAL specimens harbored C psittaci DNA. Our study demonstrates that EMZLs, accounting for the majority of primary OALs, are characterized by an indolent natural history with frequent, continuous extranodal relapses. In South Florida, OALs are not associated with C psittaci infections.

Adult↗
PubMed2005

Molecular pathogenesis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous clinicopathologic entity accounting for 30% of non-Hodgkin's lymphomas. The pathogenesis of DLBCL is complex and heterogeneous. Recent studies using analysis of global gene expression with DNA microarrays and the classical molecular approaches demonstrate presence of several DLBCL subtypes characterized by different cells of origin, cytogenetic and molecular aberrations, and distinct pathogenesis. This review summarizes the progress in understanding of DLBCL biology and presents a state-of-the-art overview of DLBCL molecular pathogenesis.

Female↗
PubMed2005

Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation.

We identified the human germinal center-associated lymphoma (HGAL) in gene-expression profiling studies of diffuse large B-cell lymphoma (DLBCL). The expression of HGAL correlated with survival in patients with DLBCL. The HGAL gene is the human homolog of M17, a mouse gene expressed specifically in normal germinal center (GC) B cells. We generated a monoclonal antibody against the HGAL protein and show that HGAL is expressed in the cytoplasm of GC lymphocytes and in lymphomas of GC derivation. Among 727 lymphomas tested by immunohistochemistry on tissue microarrays, HGAL staining was found in follicular lymphomas (103 of 107), Burkitt lymphomas (40 of 40), mediastinal large B lymphomas (7 of 8), and in DLBCLs (103 of 151). Most marginal zone lymphomas lacked HGAL staining. Lymphocyte-predominant Hodgkin lymphomas (12 of 17) and, surprisingly, classical Hodgkin lymphomas (78 of 107) were found to be positive. Hierarchical clustering of comparative immunohistologic results in DLBCLs demonstrates that the expression of HGAL is similar to 2 other GC-associated proteins, BCL6 and CD10, but different from 2 markers associated with a non-GC phenotype, MUM1/IRF4 and BCL2. The restricted expression and GC specificity of HGAL protein suggest that it may have an important role in the diagnosis of specific lymphomas, and, potentially in the identification of subtypes associated with different prognoses.

Animals↗
PubMed2005

Molecular prognostic factors in diffuse large B-cell lymphoma.

The treatment of patients with diffuse large B-cell lymphoma (DLBCL) has been guided traditionally by clinical parameters such as the Ann Arbor Staging Classification for Hodgkin's disease. Although the International Prognostic Index (IPI) represents the most widely accepted prognostic model, there is still a marked variability in outcome within identical IPI subgroups, reflecting the heterogeneity of this malignancy. Use of DNA microarray, real-time reverse transcription polymerase chain reaction, and tissue array immunohistochemistry methodologies makes the development of new classifications possible based on molecular profiling. The molecular classification of DLBCL may lead to the grouping of specific disease entities sharing similar biologic features, clinical behavior, and outcome. Once tested and validated, this new generation of prognostic models should become an integral part of the daily practice, providing valuable additional information to the currently existing clinically based predictive models. To accomplish these goals and to be in a position in which existing or new prognostic models can be easily tested and validated, there is a strong need to collect frozen and paraffin-embedded material that can be used for RNA extraction and construction of tissue arrays, respectively. Such materials should be gathered as an integral part of any planned study.

Biomarkers, Tumor↗
PubMed2005

Primary lymphoblastic B-cell lymphoma of the cranial dura mater: a case report and review of the literature.

Primary lymphomas of the cranial dura mater are rare. Mucosa-associated lymphoid tissue extranodal marginal zone lymphomas are the most common subtype of non-Hodgkin's lymphomas that present as primary cranial dura tumors. A 33 year-old male presented with a 3-month history of a growing lump in the right frontal area. Neuroimaging studies demonstrated an extra-axial, broad-based mass with a dural tail in the right frontal bone convexity. Biopsy led to the diagnosis of localized dural precursor B-cell lymphoblastic lymphoma. The patient was treated with a combination of chemotherapy and radiotherapy, achieving durable disease-free survival. This is the first report of precursor B-cell lymphoblastic lymphoma of dura mater. A review of the literature on primary lymphomas of cranial dura mater is presented. Primary lymphomas of the cranial dura mater are rare. Mucosa-associated lymphoid tissue extranodal marginal zone lymphomas are the most common subtype of non-Hodgkin's lymphomas that present as primary cranial dura tumors. A 33 year-old male presented with a 3-month history of a growing lump in the right frontal area. Neuroimaging studies demonstrated an extra-axial, broad-based mass with a dural tail in the right frontal bone convexity. Biopsy led to the diagnosis of localized dural precursor B-cell lymphoblastic lymphoma. The patient was treated with a combination of chemotherapy and radiotherapy, achieving durable disease-free survival. This is the first report of precursor B-cell lymphoblastic lymphoma of dura mater. A review of the literature on primary lymphomas of cranial dura mater is presented.

Adult↗
PubMed2004

Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas.

Diffuse large B-cell lymphomas (DLBCLs) can be subclassified into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like tumors characterized by long and short survival, respectively. In contrast to ABC-like DLBCL, GCB-like tumors exhibit high expression of components of the interleukin 4 (IL-4) signaling pathway and of IL-4 target genes such as BCL6 and HGAL, whose high expression independently predicts better survival. These observations suggest distinct activity of the IL-4 signaling pathway in DLBCL subtypes. Herein, we demonstrate similar IL-4 expression but qualitatively different IL-4 effects on GCB-like and ABC-like DLBCL. In GCB-like DLBCL, IL-4 induces expression of its target genes, activates signal transducers and activators of transcription 6 (STAT6) signaling, and increases cell proliferation. In contrast, in the ABC-like DLBCL, IL-4 activates AKT, decreases cell proliferation by cell cycle arrest, and does not induce gene expression due to aberrant Janus kinase (JAK)-STAT6 signaling attributed to STAT6 dephosphorylation. We found distinct expression profiles of tyrosine phosphatases in DLBCL subtypes and identified putative STAT6 tyrosine phosphatases-protein tyrosine phosphatase nonreceptor type 1 (PTPN1) and PTPN2, whose expression is significantly higher in ABC-like DLBCL. These differences in tyrosine phosphatase expression might underlie distinct expression profiles of some of the IL-4 target genes and could contribute to a different clinical outcome of patients with GCB-like and ABC-like DLBCLs.

Active Transport, Cell Nucleus↗
PubMed2004

Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes.

BACKGROUND: Several gene-expression signatures can be used to predict the prognosis in diffuse large-B-cell lymphoma, but the lack of practical tests for a genome-scale analysis has restricted the use of this method. METHODS: We studied 36 genes whose expression had been reported to predict survival in diffuse large-B-cell lymphoma. We measured the expression of each of these genes in independent samples of lymphoma from 66 patients by quantitative real-time polymerase-chain-reaction analyses and related the results to overall survival. RESULTS: In a univariate analysis, genes were ranked on the basis of their ability to predict survival. The genes that were the strongest predictors were LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2. We developed a multivariate model that was based on the expression of these six genes, and we validated the model in two independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power. CONCLUSIONS: Measurement of the expression of six genes is sufficient to predict overall survival in diffuse large-B-cell lymphoma.

Adolescent↗
PubMed2004

Primary diffuse large cell lymphoma of the mandible.

Primary diffuse large cell lymphoma of the mandible is a rare form of extranodal non-Hodgkin's lymphoma (NHL). Herein we present 4 cases treated at our institution over a 5-year period and review 40 cases previously reported in the English-literature. The median age at presentation is 51 years with equal distribution between males and females. At presentation the lymphoma is usually limited to the jaw (stage IE) and the most common presenting symptoms include swelling of the jaw (58%), pain (53%), and mental dysesthesia or numbness (20%). Despite symptoms of numb chin syndrome, central nervous system (CNS) involvement at presentation has not been reported. The reported therapy of this rare diffuse large cell lymphoma presentation is very heterogeneous, however majority of patients were treated with combination of chemotherapy and radiotherapy with estimated 5-year overall survival of only 60%. Multi-center prospective clinical trials are needed to determine the optimal therapeutic approach to this rare diffuse large cell lymphoma presentation.

Adult↗
PubMed2004

Somatostatin receptor scintigraphy in MALT lymphoma of the lacrimal gland treated with rituximab.

Non-gastric stage I extranodal marginal zone lymphomas of MALT are usually treated with local therapy. However, distant relapses in other extranodal sites are not uncommon suggesting under-staging of these patients using conventional image studies. Positron emission tomography (PET) scans are frequently negative in this subgroup of patients with lymphoma and therefore do not significantly contribute to the staging process. We present a case of lacrimal gland MALT lymphoma demonstrating the usefulness of somatostatin receptor scintigraphy for initial staging and evaluation of response to treatment.

Adult↗
PubMed2003

BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma.

Follicular lymphoma (FL) is characterized by a relatively indolent clinical course, but the disease often transforms into a more aggressive large cell lymphoma with a rapidly progressive clinical course. In the present study, we analyzed 41 cases of FL known to have subsequently transformed to aggressive lymphoma and an additional 64 FL samples from patients not subsequently transformed. We studied BCL6 gene rearrangement by the methodology of long-distance inverse polymerase chain reaction (LDI-PCR). Of the 41 cases known to transform, 16 (39.0%) harbored BCL6 translocation or deletion at the time of FL diagnosis. Among 64 cases not known to transform, BCL6 translocation was detected in 9 (14.1%). The prevalence of BCL6 translocation in the group known to transform was significantly higher (P =.0048). Among the transformation cases, the partners of the BCL6 translocation were identified in 13 cases and included IGH, CIITA, U50HG, MBNL, GRHPR, LRMP, EIF4A2, RhoH/TTF, and LOC92656 (similar to NAPA), whereas in the control group the BCL6 partners were IGH, CIITA, SIAT1, and MBNL. In 13 cases paired specimens before and after transformation were available. Among these paired specimens, a loss (3 cases) or a gain (1 case) of BCL6 translocation was observed after the transformation. Analysis of clonality showed that all of these cases represented the evolution of a subclone of the original tumor population. Our study demonstrated that BCL6 translocation is not necessary for transformation but that BCL6 translocation in FL may constitute a subgroup with a higher risk to transform into aggressive lymphoma.

Cell Transformation, Neoplastic↗
PubMed2003

HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma.

We have cloned and characterized a novel human gene, HGAL (human germinal center-associated lymphoma), which predicts outcome in patients with diffuse large B-cell lymphoma (DLBCL). The HGAL gene comprises 6 exons and encodes a cytoplasmic protein of 178 amino acids that contains an immunoreceptor tyrosine-based activation motif (ITAM). It is highly expressed in germinal center (GC) lymphocytes and GC-derived lymphomas and is homologous to the mouse GC-specific gene M17. Expression of the HGAL gene is specifically induced in B cells by interleukin-4 (IL-4). Patients with DLBCL expressing high levels of HGAL mRNA demonstrate significantly longer overall survival than do patients with low HGAL expression. This association was independent of the clinical international prognostic index. High HGAL mRNA expression should be used as a prognostic factor in DLBCL.

B-Lymphocytes↗