Charalampopoulou, S. (Stella)
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- Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma(2020) García-Torre, B. (Beatriz); Soler-Vila, P. (Paula); Taha, R.Y. (Ruba Y.); Beekman, R. (Renée); Rodriguez-Madoz, J.R. (Juan Roberto); El-Omri, H. (Halima); Charalampopoulou, S. (Stella); San-Jose-Eneriz, E. (Edurne); Martens, J.H.A. (Joost H. A.); Flicek, P. (Paul); Agirre, X. (Xabier); Stunnenberg, H.G. (Hendrik G.); Garate, L. (Leire); Kulis, M. (Marta); Mitsiades, C.S. (Constantine S.); Licht, J.D. (Jonathan D.); Carrasco-León, A. (Arantxa); Chapaprieta, V. (Vicente); Lara-Astiaso, D. (David); Ezponda, T. (Teresa); Ordóñez-Ciriza, R. (Raquel); Verdaguer-Dot, N. (Núria); Vilas-Zornoza, A. (Amaia); Campo, E. (Elías); Dupéré-Richer, D. (Daphné); Miranda, E. (Estibaliz); Duran-Ferrer, M. (Martí); Meydan, C. (Cem); Paiva, B. (Bruno); Vilarrasa-Blasi, R. (Roser); Gut, I. (Ivo); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Turrilas, R. (Rebeca); Clot, G. (Guillem); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Russiñol, N. (Nuria)Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
- Gene expression derived from alternative promoters improves prognostic stratification in multiple myeloma.(Springer nature, 2021) Valcárcel-García, L.V. (Luis Vitores); Amundarain, A. (Ane); Kulis, M. (Marta); Charalampopoulou, S. (Stella); Melnick, A. (Ari); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Planes-Pedreño, F.J. (Francisco Javier); Agirre, X. (Xabier); Prosper-Cardoso, F. (Felipe)Clinical and genetic risk factors are currently used in multiple myeloma (MM) to stratify patients and to design specific therapies. However, these systems do not capture the heterogeneity of the disease supporting the development of new prognostic factors. In this study, we identified active promoters and alternative active promoters in 6 different B cell subpopulations, including bone-marrow plasma cells, and 32 MM patient samples, using RNA-seq data. We find that expression initiated at both regular and alternative promoters was specific of each B cell subpopulation or MM plasma cells, showing a remarkable level of consistency with chromatin-based promoter definition. Interestingly, using 595 MM patient samples from the CoMMpass dataset, we observed that the expression derived from some alternative promoters was associated with lower progression-free and overall survival in MM patients independently of genetic alterations. Altogether, our results define cancer-specific alternative active promoters as new transcriptomic features that can provide a new avenue for prognostic stratification possibilities in patients with MM.
- Epigenetic-based differentiation therapy for acute myeloid leukemia(Springer Nature, 2024) San-Jose-Eneriz, E. (Edurne); Giménez-Camino, N. (Naroa); Rabal, O. (Obdulia); Garate, L. (Leire); Miranda, E. (Estibaliz); Gómez-Echarte, N. (Nahia); García, F. (Fernando); Charalampopoulou, S. (Stella); Saez, E. (Elena); Vilas-Zornoza, A. (Amaia); San-Martín-Uriz, P. (Patxi); Valcárcel-García, L.V. (Luis Vitores); Barrena, N. (Naroa); Alignani, D. (Diego); Tamariz-Amador, L.E. (Luis Esteban); Perez-Ruiz, A. (Ana); Hilscher, S. (Sebastian); Schutkowski, M. (Mike); Alfonso-Piérola, A. (Ana); Martinez-Calle, N. (Nicolas); Larrayoz, M.J. (María José); Paiva, B. (Bruno); Calasanz-Abinzano, M.J. (Maria Jose); Muñoz, J. (Javier); Isasa, M. (Marta); Martin-Subero, J.I. (Jose Ignacio); Pineda-Lucena, A. (Antonio); Oyarzabal, J. (Julen); Agirre, X. (Xabier); Prosper-Cardoso, F. (Felipe)Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer-promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.
- Epigenetic-based differentiation therapy for Acute Myeloid Leukemia(Springer Nature, 2024) San-Jose-Eneriz, E. (Edurne); Gimenez-Camino, N. (Naroa); Rabal, O. (Obdulia); Garate, L. (Leire); Miranda, E. (Estibaliz); Gómez-Echarte, N. (Nahia); García-Pajares, F. (Fernando); Charalampopoulou, S. (Stella); Saez, E. (Elena); Vilas-Zornoza, A. (Amaia); San-Martín-Uriz, P. (Patxi); Valcárcel-García, L.V. (Luis Vitores); Barrena, N. (Naroa); Alignani, D. (Diego); Tamariz-Amador, L.E. (Luis Esteban); Perez-Ruiz, A. (Ana); Hilscher, S. (Sebastian); Schutkowski, M. (Mike); Alfonso-Piérola, A. (Ana); Martinez-Calle, N. (Nicolas); Larrayoz, M.J. (María José); Pavia, B. (Bruno); Calasanz-Abinzano, M.J. (Maria Jose); Muñoz, J. (Javier); Isasa, M. (Marta); Martin-Subero, J.I. (Jose Ignacio); Pineda-Lucena, A. (Antonio); Oyarzabal, J. (Julen); Agirre, X. (Xabier); Prosper-Cardoso, F. (Felipe)Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.