Gonzalez, M. (Marcos)
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- Molecular profiling of immunoglobulin heavychain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients(2020) Gonzalez-Calle, V. (Veronica); Martínez-López, J. (Joaquín); Garcia-Alvarez, M. (María); Gonzalez, M. (Marcos); Gironella, M. (Mercedes); Bladé, J. (Joan); Prieto-Conde, M.I. (María Isabel); Sarasquete, M.E. (María E.); García-Sanz, R. (Ramón); Alcoceba, M. (Miguel); Medina, A. (Alejandro); Mateos, M.V. (María Victoria); Hernandez, M.T. (Miguel Teodoro); Balanzategui, A. (Ana); Puig, N. (Noemí); Barrio, S. (Santiago); Pérez-Cuenca, I. (Isabel); Lahuerta-Vargas, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Escalante, L.F. (Luis Fernando); Oriol, A. (Albert); Sureda-Balari, A. M. (Anna Maria); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); San-Miguel, J.F. (Jesús F.); Jiménez, C. (Cristina)Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavychain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.
- [Novísima geografía universal : España] [Material gráfico] : [portada] / M. Gonzalez([Barcelona : Rafael Salvatella, 2012-11-30) Gonzalez, M. (Marcos); Salvatella, Rafael; Litografía Busquet (Barcelona); Litografía Vidal (Barcelona)
- 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.
- Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma(2020) Gonzalez-Calle, V. (Veronica); Cedena, M.T. (María Teresa); Montero, J. (Juan); Martínez-López, J. (Joaquín); Garcia-Alvarez, M. (María); Gonzalez, M. (Marcos); Gironella, M. (Mercedes); Bladé, J. (Joan); Prieto-Conde, M.I. (María Isabel); Sarasquete, M.E. (María E.); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Alcoceba, M. (Miguel); Medina, A. (Alejandro); Mateos, M.V. (María Victoria); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Paiva, B. (Bruno); Oriol, A. (Albert); Chillón, M.C. (María del Carmen); San-Miguel, J.F. (Jesús F.); Jiménez, C. (Cristina)
- Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)(2018) Durie, B. (B.); Montero, J. (Juan); Gonzalez, M. (Marcos); Pontes, R. (R.); Hernández-Martín, J. (J.); Diez-Campelo, M. (M.); García-Mateo, A. (A.); Corral-Mateos, A. (A.); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Mateos, M.V. (María Victoria); Romero, A. (A.); Puig, N. (Noemí); Millacoy, P. (P.); Blanco, J.F. (J. F.); Garcés-Latre, J.J. (Juan José); Burgos, L. (Leire); García-Sanchez, O. (O.); Palomera, L. (Luis); Rodriguez-Otero, P. (Paula); Ríos-Tamayo, R. (Rafael); Dongen, J.J.M. (Jacques J. M.) van; Blanco, E. (E.); Paiva, B. (Bruno); EuroFlow-Consortium; Sanoja-Flores, L. (L.); Prosper-Cardoso, F. (Felipe); Merino, J. (Juana); San-Miguel, J.F. (Jesús F.); Pérez-Andrés, M. (M.)Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p < 0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p < 0.0001) and a shorter survival in MM patients with active disease requiring treatment (p <= 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.