Myelodysplastic Neoplasia
"To understand myelodysplasia we must study both the biology of its cells of origin and how they interact with their environment."
DR. IRENE GANAN-GOMEZ RESEARCHER. MYELODYSPLASTIC NEOPLASIA RESEARCH GROUP
Myelodysplastic syndromes (MDS) are genetically heterogeneous hematologic malignancies associated with aging and with the risk of developing acute myeloid leukemia. MDS arise with the expansion of hematopoietic stem cells with genetic and/or cytogenetic alterations in the bone marrow. Proliferation of aberrant cell clones induces ineffective differentiation, which in turn results in peripheral blood cytopenias.
MDS patients have low survival rates due to their limited therapeutic options and the fact that these, for the most part, are not curative. Among the reasons for the historical lack of effective therapies against MDS are their great genetic heterogeneity and an incomplete understanding of the mechanisms that facilitate the survival and expansion of MDS stem cells.
Our group, integrated in the Cancer Center Clínica Universidad de Navarra, investigates the cellular and molecular mechanisms that lead to the development of MDS, therapy failure and disease progression. To do so, we take a comprehensive approach, allowing us to put the mechanisms intrinsic to hematopoietic stem cells in context with the extrinsic mechanisms that enable their survival and expansion, using multidisciplinary methods and state-of-the-art techniques.
Impact of our research
Currently, the only curative therapy for MDS is bone marrow stem cell transplantation, for which only a small percentage of patients are candidates. Existing therapeutic alternatives for the remaining patients can correct the symptomatology in about half of them, but have a short-lasting effect and the appearance of resistance is associated with a very rapid progression of the disease. Characterization of the global spectrum of hematopoietic stem cell alterations and other cell lineages that lead to the onset, maintenance and progression of MDS will allow the identification of targets for the development of new therapies that can eliminate aberrant cells and prevent or slow disease progression
Dra. Irene Gañán Gómez
PGROUP LEADER
+34 948 194 700 | Ext. 81 1005 | |
iganangomez@unav.es |
To identify opportunities for therapeutic intervention in MDS
We want to understand the hematopoietic stem cell-dependent and -independent mechanisms of MDS that lead to disease onset and progression. Specifically, we ask how MDS hematopoietic stem cells evade immune system surveillance, resist conventional therapies, and malign.
All of this, in order to identify opportunities for therapeutic intervention in MDS.
To do this, we use new technologies, such as single cell transcriptomics, that allow us to identify minority populations in the bone marrow providing us with a plethora of information about them.
Objectives of the Myelodysplastic Neoplasia
Research Group
The aim of our line of research is to understand how the immune system enables the development and maintenance of the disease at different stages and to understand the mechanisms of resistance to conventional therapies by hematopoietic stem cells and disease progression.
Characterization of immune evasion mechanisms in MDS.
Identification of mechanisms of MDS progression to AML after therapy failure.
Discovery of new therapeutic targets for MDS.
Lines of research
Tumor niche modulation and immune evasion are hallmarks of cancer that have added importance in elderly patients (such as those with MDS), where an aging immune system may contribute to the formation of a tumor-permissive microenvironment. We hypothesize that the immune microenvironment of MDS patients contributes to immune escape and uncontrolled expansion of aberrant hematopoietic cell clones and, therefore, therapeutic strategies that amplify the immune response could be of value in reducing the clonal and disease burden in MDS patients.
The overall goal of this line of research is to elucidate how MDS cells escape immunosurveillance, with the ultimate goal of guiding the development of novel cellular or immune reprogramming therapies to prevent or slow MDS progression. To this end, we will study the identity, quantity and functionality of immune cells from healthy elderly patients and donors, as well as their interactions with tumor cells, and identify opportunities for immunological therapeutic intervention.
Objectives:
- Analysis of the identity and transcriptional status of immune niche cells in MDS.
- Functional characterization of the immune repertoire in MDS.
- Assessment of the immunogenic capacity of MDS stem cells.
- Identification and validation of new therapeutic targets for MDS.
Several recent studies of MDS and AML hematopoietic stem cells have revealed that neoplastic stem cells can be found in two distinct differentiation stages, one more primitive and one more granulo-monocytic (GM), which give rise to two distinct hematopoietic hierarchies.
Each of these hierarchies has been associated with distinct genetic alterations. In addition, our findings, and those of other groups, suggest that stage of differentiation confers different drug sensitivity to neoplastic cells, but it is unclear whether this is directly dependent on mutation or cell identity.
We hypothesize that the signaling pathways required for the expansion and survival of MDS stem cells with GM trajectories during disease initiation and progression are different from those required in cells with primitive trajectories. The overall objective of this line of research is to characterize GM hierarchies in MDS patients at different stages of the disease in order to identify targeted therapeutic targets. To this end, we will study trajectories at the single cell level in early and late stages of the disease, identifying aberrant stem cells and analyzing their specific oncogenic dependencies.
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Objectives:
- Transcriptomic characterization of GM hematopoietic hierarchies of MDS patients at diagnosis.
- Discrimination of oncogenic mechanisms dependent on stem cell differentiation status from those dependent on specific mutations.
- Identification of signaling pathways that regulate the survival and proliferation of MDS stem cells with GM trajectory during progression to AML.
- Validation of new therapeutic targets for patients with MDS-GM.
Meet the research team
Scientific activity of the
Myelodysplastic Neoplasia Research Group
Latest scientific publications
- Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax Apr 1, 2024 | Magazine: Clinical Cancer Research
- Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes Mar 18, 2024 | Magazine: Nature Communications
- IL-1β-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes Sep 30, 2023 | Magazine: bioRxiv
- Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma. Scientific Publication Feb 15, 2023 | Magazine: bioRxiv