Huerga-Dominguez, S. (Sofia)
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- The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes(Nature Research, 2022) Berastegui-Zufiaurre, N. (Nerea); Ainciburu-Fernández, M. (Marina); Romero, J.P. (Juan Pablo); García-Olloqui, P. (Paula); Alfonso-Piérola, A. (Ana); Philippe, C. (Céline); Vilas-Zornoza, A. (Amaia); San-Martín-Uriz, P. (Patxi); Ruiz-Hernández, R. (Raquel); Abarrategi, A. (Ander); Ordoñez, R. (Raquel); Alignani, D. (Diego); Sarvide, S. (Sarai); Castro-Labrador, L. (Laura); Lamo-Espinosa, J.M. (J. M.); San-Julian, M. (Mikel); Jimenez-Solas, T. (Tamara); Lopez-Cadenas, F. (Félix); Muntion, S. (Sandra); Sanchez-Guijo, F.M. (Fermín M.); Molero, A. (Antonieta); Montoro, M.J. (Maria Julia); Tazón-Vega, Bárbara; Serrano, G. (Guillermo); Díaz-Mazkiaran, A. (Aintzane); Hernaez, M. (Mikel); Huerga-Dominguez, S. (Sofia); Bewicke-Copley, F. (Findlay); Rio-Machin, A. (Ana); Maurano, M.T. (Matthew T.)Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients.
- Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma(American Society of Hematology (ASH Publications), 2024) Palacios-Berraquero, M.L. (María L.); Rodriguez-Marquez, P. (Paula); Calleja-Cervantes, M.E. (María Erendira); Berastegui-Zufiaurre, N. (Nerea); Zabaleta, A. (Aintzane); Burgos, L. (Leire); Alignani, D. (Diego); San-Martín-Uriz, P. (Patxi); Vilas-Zornoza, A. (Amaia); Rodríguez-Díaz, S. (Saray); Inoges, S. (Susana); Lopez-Diaz-de-Cerio, A. (Ascensión); Huerga-Dominguez, S. (Sofia); Tamariz-Amador, L.E. (Luis Esteban); Rifon, J. J. (Jose J.); Alfonso-Piérola, A. (Ana); Lasarte, J.J. (Juan José); Paiva, B. (Bruno); Hernaez, M. (Mikel); Rodriguez-Otero, P. (Paula); San-Miguel, J.F. (Jesús F.); Ezponda, T. (Teresa); Rodriguez-Madoz, J.R. (Juan Roberto); Prosper-Cardoso, F. (Felipe)Hematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CAR-T) therapies, being particularly severe among patients with relapsed or refractory multiple myeloma (MM). In this study, we characterized 48 patients treated with B-cell maturation antigen (BCMA) CAR-T cells to understand kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. We observed that overall incidence of cytopenia was 95.7%, and grade >3 thrombocytopenia and neutropenia, 1 month after infusion, was observed in 57% and 53% of the patients, respectively, being still present after 1 year in 4 and 3 patients, respectively. Baseline cytopenia and high peak inflammatory markers were highly correlated with cytopenia that persisted up to 3 months. To determine potential mechanisms underlying cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPC differentiation, promoting more immature phenotypes, which could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6) and IL-17 inhibitors. Single-cell RNA sequencing demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a decrease in the activity of key regulons involved in neutrophil and monocytic maturation (ID2 and MAFB). These results suggest that CAR-T activation induces HSPC maturation arrest through paracrine effects and provides potential treatments to mitigate the severity of this toxicity.
- Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide(Nature Research, 2024) Serrano, G. (Guillermo); Berastegui-Zufiaurre, N. (Nerea); Díaz-Mazkiaran, A. (Aintzane); García-Olloqui, P. (Paula); Rodriguez-Res, C. (Carmen); Huerga-Dominguez, S. (Sofia); Ainciburu-Fernández, M. (Marina); Vilas-Zornoza, A. (Amaia); San-Martín-Uriz, P. (Patxi); Aguirre-Ruiz, P. (Paula); Ullate-Agote, A. (Asier); Ariceta, B. (Beñat); Lamo-Espinosa, J.M. (J. M.); Acha, P. (Pamela); Calvete, O. (Oriol); Jimenez-Solas, T. (Tamara); Molero, A. (Antonieta); Montoro, M.J. (Maria Julia); Diez-Campelo, M. (Maria); Valcarcel, D. (David); Sole, F. (Francisco); Alfonso-Piérola, A. (Ana); Prosper-Cardoso, F. (Felipe); Ezponda, T. (Teresa); Hernaez, M. (Mikel); Ochoa-Álvarez, I. (Idoia)While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.