Cobaleda, C. (César)

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    Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma
    (2023) Perez, C. (Cristina); Fresquet, V. (Vicente); Maia, C. (Catarina); Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Celay, J. (Jon); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Roncador, G. (Giovanna); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Walensky, L.D. (Loren D.); Panizo, C. (Carlos); Lasater, E.A. (Elisabeth A.); Katz, S.G. (Samuel G.); Larrayoz, M. (Marta); Roa, S. (Sergio); Bergsagel, P.L. (P. Leif); Gonzalez, P. (Patricia); Botta, C. (Cirino); Ordóñez-Ciriza, R. (Raquel); Takahashi, S. (Satoru); Aguirre-Ena, X. (Xabier); Kurilovich, A. (Anna); Amann, M. (Maria); Rodriguez-Otero, P. (Paula); Llopiz, D. (Diana); Paiva, B. (Bruno); Sarobe, P. (Pablo); Campos-Sanchez, E. (Elena); Ruppert, S.M. (Shannon M.); Martínez-Cano, J. (Jorge); Larrayoz, M.J. (María J.); Revuelta, M.V. (Maria V.); Cobaleda, C. (César); Prosper-Cardoso, F. (Felipe); Etxebeste-Mitxeltorena, A. (Amaia); Calasanz-Abinzano, M.J. (Maria Jose); San-Miguel, J.F. (Jesús F.); Cerchietti, L. (Leandro); Planell, N. (Núria); Jiménez-Andrés, M. (Maddalen); Kudryashova, O. (Olga); Chesi, M. (Marta); Lasarte, J.J. (Juan José)
    The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-kappaB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of 500 mice and 1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
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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.