Sagardoy, A. (Ainara)
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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.
- Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells(Public Library of Science, 2013) Grande, L. (Lara); Huse, J.T. (Jason T.); Alonso-Roldán, M.M. (Marta María); Nogueira, L. (Lorena); Martinez-Climent, J.A. (José Ángel); Tejada-Solis, S. (Sonia); Aznar, M.A. (María Ángela); Aldaz-Arrieta, B. (Beatriz); Diez-Valle, R. (Ricardo); Fernandez-Luna, J.L. (J.L.); Raquel; Sagardoy, A. (Ainara); Guruceaga, E. (Elizabeth)Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.
- 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.