Lossos, I.S. (Izidore S.)
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- A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma(National Academy of Sciences, 2011-07-26) Fresquet, V. (Vicente); Beltran, E. (E.); Rieger, M. (Melissa); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Montes-Moreno, S. (Santiago); Gesk, S. (Stefan); Almada, L.L. (Luciana L.); Richter, J.A. (José Ángel); Raquel; Siebert, R. (Reiner); Sagardoy, A. (Ainara); Martinez-Useros, J. (Javier); Fernandez-Zapico, M.E. (Martín E.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Piris, M.A. (Miguel A.); Sesma, I. (Izaskun)The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
- LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome(Ferrata Storti Foundation, 2011) Fresquet, V. (Vicente); Bobadilla, M. (Míriam); Roman-Gomez, J. (José); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Aznar, M.A. (María Ángela); Martin-Palanco, V. (Vanesa); Raquel; Prosper-Cardoso, F. (Felipe); Robles, E.F. (Eloy Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Altobelli, G.G. (Giovanna G.); Aguirre-Ena, X. (Xabier); Smeland, E.B. (Erlend B.)BACKGROUND: LMO2 is highly expressed at the most immature stages of lymphopoiesis. In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome. The implication of LMO2 in B-cell acute lymphoblastic leukemia must still be explored. DESIGN AND METHODS: We measured LMO2 expression by real time RT-PCR in 247 acute lymphoblastic leukemia patient samples with cytogenetic data (144 of them also with survival and immunophenotypical data) and in normal hematopoietic and lymphoid cells. RESULTS: B-cell acute lymphoblastic leukemia cases expressed variable levels of LMO2 depending on immunophenotypical and cytogenetic features. Thus, the most immature subtype, pro-B cells, displayed three-fold higher LMO2 expression than pre-B cells, common-CD10+ or mature subtypes. Additionally, cases with TEL-AML1 or MLL rearrangements exhibited two-fold higher LMO2 expression compared to cases with BCR-ABL rearrangements or hyperdyploid karyotype. Clinically, high LMO2 expression correlated with better overall survival in adult patients (5-year survival rate 64.8% (42.5%-87.1%) vs. 25.8% (10.9%-40.7%), P= 0.001) and constituted a favorable independent prognostic factor in B-ALL with normal karyotype: 5-year survival rate 80.3% (66.4%-94.2%) vs. 63.0% (46.1%-79.9%) (P= 0.043). CONCLUSIONS: Our data indicate that LMO2 expression depends on the molecular features and the differentiation stage of B-cell acute lymphoblastic leukemia cells. Furthermore, assessment of LMO2 expression in adult patients with a normal karyotype, a group which lacks molecular prognostic factors, could be of clinical relevance.
- Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice(National Academy of Sciences, 2012-06-26) Garcia-Criado, F.J. (Francisco J.); Sanchez-Garcia, I. (Isidro); Gonzalez, M. (Marcos); McPhail, E.D. (Ellen D.); Peñuelas-Sanchez, I. (Ivan); Flores, T. (Teresa); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Aznar, M.A. (María Ángela); Ruiz-Roca, L. (Lucía); Sagaert, X. (Xavier); Garcia-Bragado, F. (Federico); Tousseyn, T. (Thomas); Bertolo, C. (Cristina); Siebert, R. (Reiner); Martinez-Ferrandis, J.I. (José I.); Sagardoy, A. (Ainara); Bellosillo, B. (Beatriz); Romero-Camarero, I. (Isabel); Fontan, L. (Lorena); Garcia-Cenador, M.B. (María B.); Campos-Sanchez, E. (Elena); Hernandez-Rivas, J.M. (Jesús M.); Barajas-Diego, M. (Marcos); Du, M.Q. (Ming Q.); Cobaleda, C. (César); Gonzalez-Herrero, I. (Inés); Prosper-Cardoso, F. (Felipe); Segura, V. (Víctor); Conde, E. (Eulogio); Alonso-Escudero, E. (Esther); Salar, A. (Antonio); Aguirre-Ena, X. (Xabier); Abollo-Jimenez, F. (Fernando); Vicente-Dueñas, C. (Carolina)Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.
- Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha(Informa Healthcare, 2010) Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Alizadeh, A.A. (Ash A.); Harrington, W.J. (W. J.); Lossos, C. (Chen); Ramos-González, J. (Juan Carlos); Bohen, S.P. (S.P.); Cubedo, E. (Elena)Adult T-cell leukemia-lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon alpha (IFNalpha). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT-IFNalpha therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT-IFNalpha differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT-IFNalpha therapy may provide novel insights into the mechanisms of action in ATLL.