Myeloid Pathology

"Gaining a deeper understanding of the molecular basis of myeloid pathologies is essential in order to design targeted therapies that are effective for these patients."

DR. TERESA EZPONDA ITOIZ
RESEARCHER. MYELOID PATHOLOGY RESEARCH GROUP

In recent decades, the aging of the population has led to an increase in the incidence of age-associated diseases, including myeloid neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemias (AMLs). However, the survival rates of these diseases have not improved significantly in recent years because the therapies used are not effective in eradicating these aberrant cells. Therefore, the identification of the molecular mechanisms involved in the development and progression of MDS and AMLs has become crucial in order to develop new specific and effective therapeutic approaches for these patients.

In our Myeloid Pathology research team, integrated in the Cancer Center Clínica Universidad de Navarra, we seek to understand the molecular basis underlying the aberrant hematopoietic differentiation that takes place in MDS and AML, with the ultimate goal of finding new therapeutic targets that are effective for the treatment of these patients.

To carry out our research, we have a multidisciplinary team, which combines the use of cutting-edge genomic techniques and computational analysis, to carry out a characterization of the aberrant hematopoietic cells of these patients; together with cellular and molecular biology techniques that allow us to identify, among all the alterations, those that are functionally relevant to neoplastic cells. All this is done in close collaboration with the clinical setting and with other renowned groups, both national and international.

The identification of key transcriptional lesions and transcriptional master regulators for malignant cells of myelodysplastic syndromes and water myeloid leukemia could lead to the characterization of new therapeutic targets that are effective in eliminating these cells and could improve the life expectancy of these patients.

Teresa Ezponda. investigadora principal del grupo Patología mieloide. Cima Universidad de Navarra

Dra. Teresa Ezponda

GROUP LEADER

	+34 948 194 700 \| Ext. 81 1005
	tezponda@unav.es
	Research profile

Oncology research integrated in the
Cancer Center Clinica Universidad de Navarra

Learn about the cancer center

Use of cutting-edge genomic technologies

El uso de tecnologías genómicas punteras, como los estudios de célula simple, están permitiendo conocer en mayor profundidad las bases moleculares de la patología mieloide. Grupo de Investigación de Patología Mieloide. Cima Universidad de Navarra

The use of cutting-edge genomic technologies, such as single-cell studies, is allowing us to gain a deeper understanding of the molecular basis of myeloid pathology. For example, single-cell RNA-seq analysis of hematopoietic progenitor cells from MDS patients with 5q deletion has allowed us to identify the cells that present this genetic alteration, allowing us to study, in a very precise way, its impact on the disease.

Objectives of the Myeloid Pathology
Research group

Our aim is to understand how transcriptional alterations in hematopoietic progenitors trigger myeloid differentiation disorders such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Identify transcriptional and gene regulatory pathway alterations that contribute to the development of MDS and AML.

Icono naranja con fármacos. Cima Universidad de Navarra

Identify lesions that mediate resistance to treatment of high-risk MDS.

To find new therapeutic strategies for MDS and AML.

Lines of research

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.

Hypomethylating agents (HMAs) are the treatment of choice for patients with high-risk myelodysplastic syndromes (MDS); however, most patients do not respond to these drugs or eventually relapse after a first response. Since there are no alternative therapies, understanding the mechanisms of resistance to HMAs is key to develop new therapeutic strategies that lead to better patient response.

Objectives

In this line of research we aim to:

To understand the molecular basis underlying high-risk MDS.
To identify subpopulations of cells that mediate primary or secondary resistance to HMAs, characterizing their genetic and epigenetic alterations.
etermine functionally, among all the alterations observed in resistant cells, which ones mediate resistance to HMAs.
To identify new therapeutic targets that can be used together or after treatment with HMAs to effectively eliminate these cells.

In this line of research the group also collaborates closely with national groups 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)), as well as with international groups 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.

Acute myeloid leukemia (AML) is a lethal neoplasm characterized by uncontrolled proliferation of myeloid progenitors in the bone marrow. Among AMLs, those with myelodysplasia-related changes (AML-CRM) represent a relatively new group that constitutes 48% of all adult AML cases, and is characterized by showing greater resistance to therapy and worse prognosis than other AML subtypes. Therefore, the development of new therapeutic strategies that are effective in eliminating this subtype of AML is, nowadays, a necessity. One of the main problems in the management of AML-CRM is that they constitute a highly heterogeneous group, in which, in addition to the intrinsic variability of AML, some of these patients have received previous treatment with hypomethylating agents (HMAs) for a previous state of myelodysplastic syndrome. AMHs alter the epigenome of the cells, which may affect their behavior and response to therapy; in fact, previously treated patients have a worse prognosis than untreated patients, suggesting a different molecular pathology associated with the existence of a previous treatment. Despite the great heterogeneity of AML-CRM, nowadays this type of AML is always treated in the same way, which highlights the need for personalized therapies for these patients, which are effective in the eradication of leukemic cells.

Objectives

With our research we aim to:

Identify specific transcriptomic and epigenetic alterations that characterize previously treated and untreated AML-CRM.
Characterize alterations in the activity of gene regulatory networks (transcription factors and target genes) key to the transcriptome, and thus to the leukemic phenotype of each type of AML-CRM.
To identify new therapeutic approaches for AML-CRM patients naïve and previously treated with HMAs.