Institute for Translational Medicine and Pharmacology at Mount Sinai

Led by Dr. Ronald Hoffman, the Albert A. and Vera G. List Professor of Medicine and Professor of Medicine (Hematology and Medical Oncology), leads a comprehensive research initiative that focuses on developing medical treatments for patients with myeloproliferative disorders. These disorders are rare blood cancers caused by changes in the stem cells inside bone marrow, producing an excess of red blood cells, white blood cells, or platelets. By combining laboratory-based research with direct patient care to advance understanding and treatment of rare blood cancers, the program's research priorities remain firmly grounded in the real-world needs of the patient population it serves.

Myeloproliferative Neoplasms

The research specializes in myeloproliferative neoplasms (MPNs)—a group of chronic blood cancers that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). These conditions arise from the neoplastic transformation of early hematopoietic stem cells and affect approximately 300,000 individuals in the United States. Unlike many cancer programs that focus solely on symptom management, Dr. Hoffman's research program pursues a fundamentally different approach: targeting malignant hematopoietic stem cells with combination drug therapies to deplete or even eliminate them, thereby changing the natural course of these lethal blood cancers. The program uses data generated from basic research projects as a platform to create and execute investigator-initiated phase 1/2 clinical trials.

The MPN Research Consortium

In 2003, Dr. Hoffman founded the Myeloproliferative Neoplasm Research Consortium (MPN-RC), a multi-institutional program project grant funded by the National Cancer Institute. As Principal Investigator since 2006, Dr. Hoffman leads this collaborative network of translational researchers from 13 institutions across North America. The consortium received a five-year funding renewal of $20 million from the National Cancer Institute in March 2023, bringing the consortium's continuous funding to more than $80 million since its founding.

Over the past 15 years, the initiative has resulted in four phase 1 trials, six phase 2 trials, one phase 3 trial, and more than 20 peer-reviewed published studies. The consortium's work has been instrumental in developing breakthrough treatments, including Janus kinase 2 (JAK2) inhibitors for treating myelofibrosis, and restoring the tumor suppression activity of the TP53 gene through small-molecule inhibitors of the MDM2 protein.

A critical component of the program's research, led by Huihui Li, PhD, a K01 Career Development Award recipient, focuses on evaluating and advancing JAK2 inhibitor therapies—a class of drugs that has revolutionized the treatment landscape for myeloproliferative neoplasms.

The research program pursues three interconnected objectives to advance JAK2 inhibitor therapy. First, the team is systematically assessing the effectiveness of therapeutic agents targeted directly to malignant myeloproliferative disorder stem cells, evaluating their capacity not only to reduce symptom burden but also to deplete the underlying malignant cell population. Second, investigators are exploring the complex inflammatory signaling cascades and dysregulated gene expression patterns in malignant myelofibrosis stem cells to identify vulnerabilities that can be exploited therapeutically. Understanding these molecular mechanisms is essential for rational drug design and for identifying biomarkers that predict treatment response. Third, the program is investigating novel therapeutic agents—both as single agents and in combination with JAK2 inhibitors—with the aim of embedding comprehensive biomarker studies within clinical trials to document efficacy and to stratify patients based on their molecular profiles.

Under the leadership of Yelena Z. Ginzburg, MD, this research investigates the fundamental mechanisms governing red blood cell production (erythropoiesis) and iron metabolism, translating laboratory discoveries into novel therapeutic strategies for patients with diverse hematologic and systemic disorders. Red blood cell production is intricately regulated by iron availability, and disruptions to this delicate balance underlie a wide spectrum of diseases—from conditions characterized by excessive red blood cell production to those marked by severe anemia.

A central finding from the program's research demonstrates that compensatory mechanisms within the iron regulation pathway can be therapeutically targeted to ameliorate diseases of disordered erythropoiesis. Building on this discovery, the program is currently spearheading a comprehensive investigation into how dysregulation of iron metabolism contributes to the pathophysiology of multiple conditions, including polycythemia vera (characterized by overproduction of red blood cells), myelodysplastic syndromes (bone marrow disorders with ineffective blood cell production), and β-thalassemia (a hereditary anemia resulting from defective hemoglobin synthesis). Recognizing that iron metabolism extends beyond blood disorders, the program has also expanded its research to explore the role of iron dysregulation in bone homeostasis and Alzheimer's disease—conditions in which aberrant iron accumulation or deficiency may drive disease progression.

Monoferric N Relative to Monoferric C

The program has developed novel transgenic mouse models that reveal fundamental insights into how iron-loaded transferrin molecules differentially regulate erythropoiesis and iron metabolism. Transferrin, the blood protein responsible for delivering iron to cells, can bind iron at two distinct sites, producing either monoferric N-transferrin (iron bound at the N-terminal site) or monoferric C-transferrin (iron bound at the C-terminal site). Using these transgenic models, researchers have demonstrated that these two forms exert dramatically different effects on red blood cell production and systemic iron balance. Importantly, preliminary data reveal that monoferric N-transferrin—but not monoferric C-transferrin—provides significant therapeutic benefits when expressed in β-thalassemic mice, a model of the inherited blood disorder characterized by defective hemoglobin production and profoundly ineffective erythropoiesis. By elucidating the specific molecular mechanisms through which different transferrin iron-loading states influence erythropoiesis, this work represents an advance in understanding how apo-transferrin (iron-free transferrin) may ameliorate ineffective erythropoiesis in β-thalassemia patients, opening new avenues for developing targeted therapies that could improve red blood cell production and reduce the need for chronic blood transfusions.

In a complementary investigation conducted in collaboration with the Mount Sinai Bone Program, our research has uncovered an unexpected protective role for erythroferrone (ERFE) in bone health. ERFE is a hormone secreted by developing red blood cells that suppresses hepcidin production, thereby increasing iron availability for hemoglobin synthesis. While ERFE's role in promoting iron overload has been well-established in β-thalassemia—where massive expansion of ineffective erythropoiesis drives excessive ERFE production and hepcidin suppression—this research reveals that ERFE also exerts significant osteoprotective effects, strengthening bone structure and preventing bone loss. This discovery carries critical clinical implications, as therapeutic agents targeting the ERFE pathway are currently in development for β-thalassemia patients to reduce iron overload, yet many of these patients suffer from severe skeletal complications including thinning of cortical bone and decreased bone mineral density. Understanding ERFE's dual role in both iron metabolism and bone health will be essential for designing optimal therapeutic strategies that address iron overload without inadvertently worsening skeletal health, and may even suggest approaches to simultaneously improve both hematologic and bone outcomes in this vulnerable patient population.

Treatment for Polycythemia Vera

A particularly promising avenue of research focuses on evaluating innovative therapeutic approaches for polycythemia vera, including hepcidin-mimetic agents such as rusfertide and activin receptor ligand traps. Hepcidin, the body's master regulator of iron metabolism, controls the absorption of dietary iron and the release of stored iron into circulation. In polycythemia vera, the excessive production of red blood cells creates an enormous demand for iron, paradoxically leaving most patients iron deficient despite their elevated red blood cell counts. By administering a synthetic hepcidin mimetic, rusfertide restricts iron availability for red blood cell production, thereby normalizing red blood cell levels without requiring frequent phlebotomy—the current standard of care that many patients find burdensome and that fails to address the underlying disease biology while exacerbating iron deficiency.

This translational work builds directly on the program's preclinical research demonstrating the effectiveness of hepcidin-mimetics in mouse models of polycythemia vera. The success of these laboratory studies provided the scientific foundation for advancing rusfertide into clinical trials, where it has shown promising efficacy and safety profiles. Notably, rusfertide has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA)—a distinction reserved for therapies that demonstrate substantial improvement over existing treatments for serious or life-threatening conditions. If approved, rusfertide would represent the first hepcidin-based therapy for a malignant disease, establishing a new therapeutic paradigm that targets the iron metabolism defects underlying polycythemia vera rather than merely managing its symptoms. This approach holds the potential to significantly improve quality of life and reduce complications for patients who currently face limited treatment options beyond phlebotomy and cytoreductive therapies.

Under the leadership of Dr. Glassberg, this is an offshoot program of the Mount Sinai Center for Sickle Cell Disease, which pursues several avenues of research to improve the lives of patients with sickle cell disease. The Center's network of laboratories investigates biomarkers for disease severity and vaso-occlusive crises, evaluates novel agents for preventing and treating complications, explores the role of the gut microbiome in driving organ injury, and develops in vivo gene therapy approaches using lipid nanoparticle delivery of CRISPR gene editing systems in collaboration with the Biopharmaceutical and Nanomedicine Development Core. The Center also oversees large-scale, multi-site research projects, including REAL Answers—a 10-center, 1,000-patient observational study that uses a technique called target-trial emulation to determine which new sickle cell medications work best, in which combinations, and for which patients. The overarching goal is to advance sickle cell science to facilitate personalized treatment regimens today and achieve curative therapies in the future.

The network of labs funded by this Center studies biomarkers for disease severity and vaso-occlusion, novel agents for the prevention and treatment of complications, the role of the gut microbiome in driving organ injury, and in vivo gene therapy cures using lipid nanoparticle delivery of CRISPR gene editing systems on collaboration with the Biopharmaceutical and Nanomedicine Development Core. The Center also oversees large-scale, multi-site research projects, including a 10-center, 1,000-patient, observational study called REAL Answers, where investigators use a technique called target-trial emulation to determine which new sickle cell medications work best, in which combinations, and for which patients. The overall goal is to advance sickle cell science to facilitate personalized treatment regimens now, and cure the disease in the future.

Role of Gut Microbiota in Organ Damage Among Sickle Cell Patients

This research is investigating a paradigm-shifting hypothesis: that organ damage in sickle cell disease, while long attributed primarily to the sickling of red blood cells, may be independently driven by alterations in the gut microbiome. This initiative was inspired by compelling data showing that disruption of the microbiota with broad-spectrum antibiotics led to improvements in chronic organ damage and enhanced sepsis survival in sickle cell disease models. Building on these observations, investigators aim to identify specific types of gut bacteria and microbiome-related mechanisms that trigger chronic inflammation and organ damage in sickle cell disease. Additionally, the team is exploring whether manipulating dietary elements—such as iron intake—can restore a healthy gut microbiome (eubiosis) and reduce disease burden. This work represents a novel approach to understanding and treating sickle cell disease complications, potentially opening new therapeutic avenues that target the microbiome-organ injury axis rather than focusing exclusively on the hematologic abnormalities.