Salar, A. (Antonio)

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    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.
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    Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group
    (2016) López-Guillermo, A. (Armando); González-Barca, E. (Eva); Ocio, E.M. (Enrique M.); Montes-Moreno, S. (Santiago); Martin, A. (Alejandro); Caballero, D. (Dolores); Canales-Albendea, M. A. (Miguel Ángel); Redondo, A. M. (Alba M.); Salar, A. (Antonio); Dlohuy, I. (Iván)
    Diffuse large B-cell lymphoma (DLBCL) patients failing rituximab-containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21-day cycle, in combination with R-ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem-cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose-limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR-ESHAP cycles resolved appropriately and no grade 4–5 non-haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow-up of 24·6 (17·4–38·2) months, the 2-year progression-free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR-ESHAP regimen is feasible and yields encouraging outcomes.