Our research is focused on the study of the cellular and molecular biology of hematologic malignancies (blood cancers), and our ultimate goal is to apply our findings to discover new and better therapies that can positively impact the outcome of our patients. Specifically, we currently study disorders that are frequent in elderly patients.
Myelodysplastic syndromes (MDS) are a group of heterogeneous disorders that have in common the inability to normally produce blood cells in the bone marrow (inefficient hematopoiesis), resulting in the progressive loss of one or more blood cell types (cytopenias). MDS originate through the accumulation of genetic alterations (mutations or chromosome aberrations) in blood-producing stem cells (hematopoietic stem cells, HSCs), which is a process that may take several years in the life of an adult individual to manifest symptoms. Patients with MDS currently have limited therapeutic choices, which may have only a transient effect after which the progression of the disease is commonly a fatal event.
In our lab, our efforts in MDS research are focused on improving the understanding of the molecular and biological mechanisms underlying MDS, with an emphasis on the functional, molecular and genetic characterization of the HSCs responsible for the origin, maintenance and progression of MDS at different stages of the disease: when patients present with mild clonal cytopenias that may predict future MDS development (clonal cytopenias of undetermined significance, CCUS), at the time of diagnosis of MDS and after failure to first-line therapies and disease progression to secondary leukemia. We aim to identify key oncogenic mechanisms in MDS HSCs that represent vulnerabilities that can be therapeutically targeted to prevent the evolution of MDS with early interventions or to stop the disease progression after failure of conventional therapies. To do so, we make use of techniques such as primary cell culturing, animal modelling, multiparameter flow cytometry, next-generation sequencing and state-of-the-art single-cell RNA sequencing technologies.
The prevalence of multiple myeloma (MM), already the second-most common hematological malignancy worldwide, will grow by almost 60% by 2030, making the disease an increasingly important public health challenge. In the last decade, MM patients’ clinical outcomes have improved owing to the introduction of novel agents, which have doubled these patients’ overall median survival duration. However, the expected survival duration for patients with high-risk disease is still only about 2-3 years, probably partly because available agents were not developed with an understanding of the pathobiology underlying this aggressive phenotype. The amplification of chromosome 1q21 in MM cells confers an adverse prognosis, and its prevalence approaches 30% of de novo and 70% of relapsed MM, making it the most common high-risk MM molecular subtype. In our lab, we aim to investigate the biological and molecular mechanisms behind the 1q21 amplification’s contribution to high-risk MM with the overall goal of identifying a novel target for treatment approaches that can be translated to the clinic to improve the outcomes for this subgroup of patients. DNA damage resistance is a major barrier to effective DNA-damaging anticancer therapy in MM. Our group focus on understanding the molecular mechanism of DNA repairs that contribute to MM resistance which undergoes an adaptive metabolic rewiring to restore energy balance and promotes cell survival in response to DNA damage. We perform in vitro functional validation studies using a panel of genomically characterized human 1q21 MM cell lines, primary MM samples and MM dissemination models that recapitulate the disseminated nature of MM and the features of its bone and organ metastases. We use multiple techniques and leading-edge technologies including CRISPR/cas9 screening, antisense nucleotide technology, RNA-seq, scRNA-seq, metabolomic analysis and transmission electron microscopy (TEM) in our studies to address specific questions and elucidate new therapeutic approaches to targeting MM resistance and improving the outcomes of MM patients whose disease becomes refractory to therapeutics which are currently approved.
DNA damage is a major driver of stem cell functional decline. One reservoir of persistent DNA damage signaling is telomere erosion2, which progresses over the human lifespan.
Telomere erosion can be accelerated by pathogenic germline variants in genes involved in telomere maintenance. The molecular mechanisms that drive hematopoietic stem cell (HSC) functional decline under conditions of telomere shortening are not completely understood.
In light of recent advances in single-cell technologies, we sought to redefine the transcriptional andepigenetic landscape of mouse and human hematopoietic stem cells (HSCs) under telomere attrition, such as that induced by pathogenic germline variants in telomerase complex genes.
We revealed that telomere attrition maintains HSCs in a state of persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Telomerase reactivation completely restored HSC transcriptional homeostasis at the single-cell level, overcame enhanced megakaryocytic differentiation, and significantly ameliorated HSCs’ repopulation capacity in the setting of competitive transplantation, suggesting that HSCs’ function can be restored upon telomere damage resolution. Mechanistically, we showed that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes IFN signaling activation in telomere-dysfunctional HSCs and these cells’ aberrant differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of HSCs by inducing apoptosis, autophagy, or senescence and suggests that early intervention targeting the IFI16 signaling axis can prevent HSC functional decline in conditions affecting telomere maintenance.