Translational Hematology

Myelodysplastic syndromes (MDS) are characterized by inefficient hematopoietic differentiation, resulting in the deficiency of one or more mature blood cell types. Since genetic lesions fail to fully explain this aberrant differentiation, in our line of research we explore transcriptional alterations in order to better understand the molecular basis of this disease and to design new therapeutic strategies that are effective for these patients.

Objectives

The main objectives of this research line are:

• Characterization of the transcriptional alterations suffered by the cells of origin of the disease, hematopoietic stem cells, in aging and MDS.
• Identification of transcriptional dynamics altered throughout the early stages of hematopoietic differentiation in MDS.
• Characterization of the heterogeneity of MDS patients by single cell studies.
• Identification of new therapeutic targets for specific subgroups of MDS patients.
• To develop this line of research the group counts with national collaborations within the Spanish group of myelodysplastic syndromes (GESMD) (María Diez Campelo (University Hospital of Salamanca), David Valcárcel (Val d'Hebron), Francesc Solé (Joseph Carreras Institute)), and international collaborations (Kevin Rouault-Pierre and Ana Rio (Barts Institute), Luca Malcovati (University of Pavia). In addition, the group collaborates closely with other CIMA groups, as well as with several physicians from the hematology service of the CUN. 

Our main objective is to understand the molecular mechanisms and different cellular interactions involved in CAR-T therapies. We combine multiparametric flow cytometry, multi-omics technologies, artificial intelligence and advanced gene editing technologies, to comprehensively understand, from patient samples and relevant animal models, the biological processes governing CAR-T cell response and to identify vulnerabilities that can be modulated to improve CAR-T cell efficacy.

Objetives:

• Generate a comprehensive multi-omic map of CAR-T cells, immune cells and TME from patient and animal models treated with CAR-T therapies.
• Understand the interactions between CAR-T cells and other immune populations of the TME.
• Identify regulatory and/or metabolic alterations associated to the efficacy of CAR-T therapies using machine learning methods.
• Identify and validate vulnerabilities and tumor resistance mechanisms for the development of improvement CAR-T therapies.

The tissue and organ organization characteristic of metazoans is closely dependent on homo- and heterotypic interactions between different cell types. However, our knowledge of tissue organization remains limited. Stem cell systems and their niches are highly controlled microenvironments that offer a unique opportunity to advance such knowledge. Reductionist approaches have proven highly useful for dissecting the complexity of stem cell niches in a unidirectional fashion. However, these approaches fail to recognize the complex three-dimensional structure of tissue.
In the laboratory, we are interested in understanding the different levels of organization and cellular relationships that occur in the bone marrow (BM) niche in homeostasis and after neoplastic transformation. To this end, we employ a systems biology strategy combined with the use of genetically modified animals, multi-parametric flow cytometry and multi-omics technologies.
Another major interest of our laboratory is the development of hematopoietic stem cell mobilization regimens, as well as the development of non-genotoxic conditioning agents that allow the use of hematopoietic progenitor transplantation in monogenic diseases and congenital and acquired immunodeficiencies.

Objectives:

• Define the cellular and molecular complexity of the MO niche.
• To delineate the homo- and heterotypic cellular interactions that define the functioning of the BM niche.
• Describe the cellular and molecular changes that occur in the OM following neoplastic transformation.
• Validate new therapeutic dependencies in leukemias resulting from their relationship with the cells of the OM microenvironment.

The tissue and organ organization characteristic of metazoans is closely dependent on homo- and heterotypic interactions between different cell types. However, our knowledge of tissue organization remains limited. Stem cell systems and their niches are highly controlled microenvironments that offer a unique opportunity to advance such knowledge. Reductionist approaches have proven highly useful for dissecting the complexity of stem cell niches in a unidirectional fashion. However, these approaches fail to recognize the complex three-dimensional structure of tissue.
In the laboratory, we are interested in understanding the different levels of organization and cellular relationships that occur in the bone marrow (BM) niche in homeostasis and after neoplastic transformation. To this end, we employ a systems biology strategy combined with the use of genetically modified animals, multi-parametric flow cytometry and multi-omics technologies.
Another major interest of our laboratory is the development of hematopoietic stem cell mobilization regimens, as well as the development of non-genotoxic conditioning agents that allow the use of hematopoietic progenitor transplantation in monogenic diseases and congenital and acquired immunodeficiencies.

Objectives:

• Define the cellular and molecular complexity of the MO niche.
• To delineate the homo- and heterotypic cellular interactions that define the functioning of the BM niche.
• Describe the cellular and molecular changes that occur in the OM following neoplastic transformation.
• Validate new therapeutic dependencies in leukemias resulting from their relationship with the cells of the OM microenvironment.