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Garrido-Ruiz M.C.,Hospital Universitario12 Of Octubre | Rodriguez-Pinilla S.M.,Lymphoma Group | Perez-Gomez B.,Carlos III Institute of Health | Rodriguez-Peralto J.L.,Hospital Universitario12 Of Octubre
Journal of Cutaneous Pathology | Year: 2010

Background: WT1, first recognized as a tumor suppressor gene involved in the development of Wilms' tumor, may have apparently contradictory findings and functions. As WT1 has been identified as a molecular target for cancer immunotherapy, immunodetection of WT1 in tumor cells has become an essential step in cancer studies. Methods: We compare the expression of this protein among different types of melanocytic nevi and among stages in primary melanoma progression. Tissue microarrays containing normal tissues and 271 primary melanocytic lesion samples (163 primary melanomas and 108 nevi) were studied by immunohistochemistry using monoclonal antibody against WT1. Results and Discussion: The present study shows these: 1. WT1 protein is predominantly expressed in the cytoplasm of the neoplastic cells. 2. A higher rate of WT1 staining in melanocytic nevi against melanomas has been observed. 3. WT1 expression is increased in advanced stages of melanoma progression: a significant (p < 0.05) increase of expression of WT1 was detected in vertical cases 46.5% vs. radial cases 16.0%, in high levels of Clark (IV, V) 57.4% vs. low levels (I, II, III) 33.0% and when comparing depth of invasion within thickness subgroups. 4. Finally, this study establishes an association of WT1 protein expression with shorter overall survival in melanoma. Garrido-Ruiz MC, Rodriguez-Pinilla SM, Pérez-Gómez B, Rodriguez-Peralto JL. WT 1 expression in nevi and melanomas: A marker of melanocytic invasion into the dermis. © 2009 John Wiley & Sons A/S.


Martin-Perez D.,Lymphoma Group | Sanchez E.,Hospital Nuestra Senora del Prado | Maestre L.,Monoclonal Antibodies Unit | Suela J.,Cytogenetics Unit | And 6 more authors.
American Journal of Pathology | Year: 2010

Polycomb proteins are known to be of great importance in human cancer pathogenesis. SUZ12 is a component of the Polycomb PRC2 complex that, along with EZH2, is involved in embryonic stem cell differentiation. EZH2 plays an essential role in many cancer types, but an equivalent involvement of SUZ12 has not been as thoroughly demonstrated. Here we show that SUZ12 is anomalously expressed in human primary tumors, especially in mantle cell lymphoma (MCL), pulmonary carcinomas and melanoma, and is associated with gene locus amplification in some cases. Using MCL as a model, functional and genomic studies demonstrate that SUZ12 loss compromises cell viability, increases apoptosis, and targets genes involved in central oncogenic pathways associated with MCL pathogenesis. Our results support the hypothesis that the abnormal expression of SUZ12 accounts for some of the unexplained features of MCL, such as abnormal DNA repair and increased resistance to apoptosis. Copyright © American Society for Investigative Pathology.


Martin-Perez D.,Lymphoma Group | Piris M.A.,Lymphoma Group | Sanchez-Beato M.,Lymphoma Group
Blood | Year: 2010

The Polycomb group (PcG) of proteins is a major mechanism of epigenetic regulation that has been broadly linked to cancer. This system can repress gene expression by chromatin modification and is essential for establishing cell identity. PcG proteins are important for stem cell function and differentiation and have a profound impact during hematopoiesis. In recent years, several published studies have deepened our knowledge of the biology of the PcG in health and disease. In this article, we review the current understanding of the mechanisms of PcG-mediated repression and their relation to DNA methylation, and we discuss the role of the PcG system in hematopoiesis and hematologic malignancies. We suggest that alteration of different PcG members is a frequent event in leukemia and lymphomas that confers the stem cell properties on tumor cells. Thus, drugs targeting Polycomb complexes could be useful for treating patients with these diseases. © 2010 by The American Society of Hematology.


Ellyard J.I.,Australian National University | Chia T.,Australian National University | Rodriguez-Pinilla S.-M.,Fundacion Jimenez Diaz | Martin J.L.,Australian National University | And 10 more authors.
Blood | Year: 2012

Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (T FH) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the "san" allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of T FH cells preceded tumor development, and clonal rearrangements in the TCR-β genes were present in most tumors. Furthermore, T FHcells exhibited increased clonality compared with non-T FH cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent T FH development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a T FH-derived origin. Roquin san/+mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated T FH cells or their consequences. © 2012 by The American Society of Hematology.


Wahlin B.E.,Karolinska Institutet | Aggarwal M.,Karolinska Institutet | Aggarwal M.,Lymphoma Group | Montes-Moreno S.,Lymphoma Group | And 6 more authors.
Clinical Cancer Research | Year: 2010

Purpose: The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors. Experimental Design: Seventy follicular lymphoma patients with extreme clinical outcome ("poor" and "good" cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in ≤5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used. Results: Independently of the Follicular Lymphoma International Prognostic Index, CD4+ cells were associated with poor outcome and programmed death-1-positive and CD8+ cells were associated with good outcome. The prognostic values of CD4+ and programmed death-1-positive cells were accentuated when they were follicular and that of CD8+ cells were accentuated when they were interfollicular. Follicular FOXP3+ cells were associated with good outcome and interfollicular CD68+ cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome. Conclusion: There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets. ©2010 AACR.


Churchill H.R.O.,Stanford University | Roncador G.,Lymphoma Group | Warnke R.A.,Stanford University | Natkunam Y.,Stanford University
Human Pathology | Year: 2010

Recent studies have exploited an antibody directed against programmed death 1 expressed by follicular helper T-cells in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma. We had previously described clinically relevant, variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma and, in this study, sought to address the diagnostic utility of programmed death 1 in comparison with CD57 in variant nodular lymphocyte predominant Hodgkin lymphoma. Immunohistologic staining for programmed death 1 was carried out on biopsies of 67 patients with variant nodular lymphocyte predominant Hodgkin lymphoma. Thirty-four additional cases of nodular lymphocyte predominant Hodgkin lymphoma with associated diffuse areas, de novo T-cell and histiocyte-rich large B-cell lymphoma, and lymphocyte-rich classic Hodgkin lymphoma were also studied. Our results show that programmed death 1 positivity was found in the majority of nodular lymphocyte predominant Hodgkin lymphoma cases with a classic nodular architecture (87%) as compared with 50% for CD57 and was particularly helpful in identifying extranodular large atypical cells. Nodular lymphocyte predominant Hodgkin lymphoma with diffuse areas showed a gradual decrease in programmed death 1 reactivity from nodular to diffuse areas, although a significant proportion (40%-50%) of cases retained programmed death 1 positivity also in diffuse areas. In addition, T-cell and histiocyte-rich large B-cell lymphoma and lymphocyte-rich classic Hodgkin lymphoma displayed programmed death 1 positivity in a significant subset of cases (33%-40%). In conclusion, our study supports the utility of programmed death 1 in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and shows greater sensitivity of staining of programmed death 1 as compared with CD57 across all variants of nodular lymphocyte predominant Hodgkin lymphoma. Loss of programmed death 1 reactivity did not correlate with diffuse areas, progression, or the ability to differentiate nodular lymphocyte predominant Hodgkin lymphoma from T-cell and histiocyte-rich large B-cell lymphoma. These findings suggest the need for continued vigilance in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and its immunoarchitectural variants as well as related lymphomas in their differential diagnosis. © 2010 Elsevier Inc.


Gomez-Abad C.,Lymphoma Group | Pisonero H.,Lymphoma Group | Pisonero H.,Hospital Universitario Marques Of Valdecilla | Blanco-Aparicio C.,Experimental Therapeutics Programme | And 11 more authors.
Blood | Year: 2011

PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4EBP1( Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. © 2011 by The American Society of Hematology.


Herrera-Merchan A.,Stem Cell Aging Group | Cerrato C.,Stem Cell Aging Group | Luengo G.,Genomic Unit | Dominguez O.,Genomic Unit | And 3 more authors.
Cell Cycle | Year: 2010

Hematopoietic stem cells (HSCs) are defined by their exclusive capacity to both self-renew and to give rise to multipotent progenitors (MPPs) that in turn differentiate into the mature blood cell lineages. The tumor suppressor p53, in addition to its role in the regulation of the cell cycle, plays an important role in HSC self-renewal, although it has not fully resolved. Here we report that in super-p53 mice (sp53), which carry one extra gene dose of p53, the miR-33 is downregulated in HSCs and highly expressed in MPPs. Transplantation assays of miR-33-transduced sp53 HSC results in a significant acquisition of repopulating capacity and a decrease of recipients survival. Moreover, high levels of miR-33 represses the endogenous level of p53 protein in murine embryonic fibroblasts (MEFs), leads both to neoplastic transformation and anchorage independent growth of MEFs, and displays a decrease of apoptotic response using tumor-derived cell lines. Accordingly, we demonstrate that miR-33-mediated downregulation of p53 is dependent on the binding of miR-33 to two conserved motifs in the 3′UTR of p53. together, these data show that the miR-33 modifies HSC repopulating efficiency of sp53 mice by impairing the p53 function. Defining the role of miR-33 in controlling the HSC self-renewal through p53 may lead to the prevention and treatment of hematopoietic disorders. © 2010 Landes Bioscience.


Montes-Moreno S.,Lymphoma Group
Advances in Hematology | Year: 2011

Thomas Hodgkin's and Samuel Wilks first recognized Hodgkin disease in the first half of the 19th century. Initially described as lymphogranulomatosis, it was later recognized to be a lymphoid neoplasm derived from B cells and was classified on the basis of its histopathological features. Hodgkin lymphomas are now regarded as encompassing two clearly defined entities according to the WHO classification: nodular lymphocyte-predominant Hodgkin Lymphoma (NLPHL) and classical Hodgkin Lymphoma (CHL). This paper focuses on the current knowledge about the biological features that characterize both NLPHL and CHL, highlighting those relevant to correct pathological diagnosis and those that might be associated with patient outcome. Copyright © 2011 S. Montes-Moreno.


News Article | February 15, 2017
Site: www.prweb.com

The Lymphoma Research Foundation (LRF) – the nation’s largest non-profit organization devoted exclusively to funding innovative lymphoma research and serving the lymphoma community through a comprehensive series of education programs, outreach initiatives and patient services – will celebrate the 10th Annual Love to Find a Cure Restaurant Revue at the Depot in downtown Minneapolis on Thursday, February 9, 2017. This year’s 10th annual tasting event will bring together top area chefs and restaurants, including the Blue Door Pub, Bogart’s Doughnut Co., Brie Cater, Izzy’s Ice Cream, Mediterranean Cruise Café, Nothing Bundt Cakes, Pharoah’s Gyros, and Red Cow Restaurant and Bar. Returning to the Depot in the Historic Mill and Riverfront Districts in downtown Minneapolis, the 10th anniversary of the Love to Find a Cure will feature a program including keynote addresses, live and silent auctions, and a special awards ceremony honoring local lymphoma survivors. Recipients of the 2017 LRF Inspiration Award include members of the Knockouts, one of Minnesota’s most successful Lymphoma Walk teams, Jessica Deutsch, Melissa Furch, Jeanne Morris and Jim Taglia, all of whom are lymphoma survivors. “Walking as a member of the Knockouts at the Minneapolis Lymphoma Walk has empowered me to help provide hope to my fellow lymphoma survivors in the Twin Cities and beyond,” said Jessica Deutsch, a five-year lymphoma survivor and recipient of this year's Inspiration Award. “All of my teammates and I are thrilled to be a part of this special 10th annual Love to Find a Cure event and are incredibly inspired by this tremendous show of support for a cure.” “For ten years, the Love to Find a Cure event has not only attracted the top talent in the Minneapolis food scene, but has also been a gathering point for the Twin Cities lymphoma community, providing hope to all those impacted by blood cancer,” said Dr. Thomas M. Habermann, Chair of the Mayo Clinic Lymphoma Group and Chair Elect of the LRF Scientific Advisory Board. “The generosity of our partners and supporters enables us to raise these critical funds for blood cancer research, and we look forward to another decade of continued partnership to help find a cure.” Limited sponsorship opportunities are still available, and individual tickets can be purchased for $150.00 per ticket at http://www.lymphoma.org/LoveTwinCities. For more information, please contact Taylor Zitay Kahn, Director of Distinguished Events, at (646) 465-9103 or tzitay(at)lymphoma(dot)org. About the Lymphoma Research Foundation The Lymphoma Research Foundation (LRF) is the nation’s largest non-profit organization devoted to funding innovative research and serving the lymphoma community through a comprehensive series of education programs, outreach initiatives and patient services. To date, LRF has awarded nearly $60 million in lymphoma-specific research. For additional information on LRF’s research, education and services, visit lymphoma.org.

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