Our Research
Red cell disorders affect more than a billion people worldwide, are a significant cause of morbidity and mortality, and lead to a substantial economic burden. Our research is focused on erythropoiesis and how this process goes awry in disorders such as Diamond-Blackfan Anemia (DBA), sickle cell disease (SCD), and anemia of inflammation (AoI).
We are involved in translational research and collaborate with the DBA Registry and Northwell Health's sickle cell program.
Normal Erythropoiesis
One of the major goals of our laboratory is to understand how erythropoiesis is regulated during development and at steady state, and how different regulated pathways coexist, leading to the formation of a functional red cell with a properly assembled membrane and a defined hemoglobin concentration. We use different mouse models and in vitro culture systems to fully explore erythropoiesis at the progenitor and precursor stages.
Among our major recent discoveries, we highlighted developmental differences between neonatal and adult human erythropoiesis (Yan et al., 2017). Based on these findings, we have been able to provide a revised immunophenotyping of the erythroid progenitor continuum (Yan et al., 2021). In collaboration with Drs. Gallagher and Narla of the New York Blood Center, this led us to the characterization of four populations of erythroid progenitors (EP1 through EP4) and an explanation of why steroids only act in adult progenitors.
We are now dissecting the signaling pathways involved in the mechanisms leading to normal differentiation from EP1 to EP4. Among those, we are particularly interested in cell cycle regulation.
Erythromyeloblastic Islands
In collaboration with Dr. Theodosia Kalfa’s group at Cincinnati Children’s Hospital Medical Center, we recently described the structure of the erythroblastic niche in the mouse bone marrow (Seu et al., 2018)and are now extending these studies to humans. We demonstrated that these islands support both erythropoiesis and granulopoiesis. Differentiation of these cells occurs around a central macrophage, with erythropoiesis being the main lineage supported at steady state.
However, in anemia due to defective erythropoiesis, we observed an imbalance towards granulopoiesis (Romano et al., 2022). We are investigating the mechanisms underlying these processes, focusing on anemia of inflammation and sickle cell disease.
With regards to the central macrophage, its identity remains unclear due to a heterogeneity of populations existing within the marrow and difficulties purifying those. Part of our studies is aimed at resolving this heterogeneity.
Erythropoietic Failure in DBA
Diamond Blackfan Anemia (DBA) is a rare, inherited bone marrow failure syndrome, mostly observed in children and usually presenting within the first year of life. DBA is characterized by a dramatic decrease in production of red blood cells. While tremendous progress has been made in the field, many questions remain. Among those, it is still unclear why the disease does not manifest prior to birth. This question has been difficult to answer so far due to a lack of animal models that fully recapitulate the clinical features of the disease. One of the main avenues of research in the lab is to develop new models of DBA to answer these questions.
Cancer Predisposition in Children With DBA
In addition to the anemia, patients with DBA experience short stature and are more prone to develop cancers, notably a cancer of the bone known as osteogenic sarcoma. Osteogenic sarcoma is in fact the most common bone tumor. Even though osteogenic sarcoma is a relatively common pediatric solid tumor, very little is known about how and why it develops.
If the disease is localized, the long-term survival rate is 70 to 75%. However, if the disease is metastatic (usually to the lungs or other bones) at diagnosis, the long-term survival rate is only 30%. Unfortunately, these statistics have not changed in decades. Existing therapies include complex and often function-limiting surgery and aggressive chemotherapy. There is, therefore, a strong need to better understand this form of childhood cancer, in order to improve existing treatments and increase cure rates. We are investigating the mechanism by which this cancer develops in children with DBA. Specifically, we are exploring the hypothesis that this cancer can result from genetic mutations in ribosomal proteins.
Reactivation of Fetal Hemoglobin in SCD
The only FDA-approved drug for the treatment of sickle cell disease is hydroxyurea. Hydroxyurea leads to the production of fetal hemoglobin, which is beneficial for patients affected by sickle cell disease. However, hydroxyurea is modestly effective, and there is a need for the development of additional drugs.
We published part of the mechanism of action of pomalidomide during human erythropoiesis (Dulmovits et al., 2017). These studies have direct clinical relevance since pomalidomide reactivates fetal hemoglobin production in hematopoietic progenitors from both normal and sickle cell disease patients and is already FDA-approved for the treatment of multiple myeloma. We are now investigating how pomalidomide coordinately downregulates multiple γ-globin gene repressors and investigating its potential involvement at the niche level, using the Townes mouse model of sickle cell disease.
Erythropoiesis in AoI
Anemia of inflammation is extensively studied, and tremendous progress has been made towards our understanding of this condition. However, much less is known about anemia in sepsis survivors. In collaboration with Dr. Kevin Tracey, we conducted a study in murine sepsis survivors and found that HMGB1, a known mediator of inflammation in sepsis survivors, is also involved in the development of the anemia observed in these animals (Valdés-Ferrer et al., 2015; Dulmovits et al., 2022). We further observed that the erythroblastic islands are impaired in animals experiencing anemia of inflammation.
Interested?
We are looking for motivated postdocs and students! Contact us if you would like to learn more.