Controlling the Niche to Control Clonal Hematopoiesis

Over seven million people in the United States have acquired pathogenic mutations in their blood stem cells, known as “clonal hematopoiesis” (CH), which increases their risk for life-shortening, strokes, heart and lung disease and blood cancers. Expansion of the mutated stem cells is the root cause of these risks. While inflammation and other hematopoietic stressors can favor the mutated blood stem cells, it is not exactly clear why this is or how to block it. Much has been learned about how the cancer-causing mutations act in blood forming cells but little is known about how mutated blood forming stem cells and their progeny reorganize the local environment, or niche, in which they live. Our research has found that during periods of high blood cell demand—such as infections, bleeding, or after myelosuppressive chemotherapy—the stem cell niche, “switches on” to support stem cell expansion and increased blood cell production. Similar changes are present in CH- affected marrow. Additionally, we've discovered signals that actively “switch off” the niche when the demand for blood cells returns to normal, a process that fails in CH. The long-term goal of this research is to develop new approaches to control niche activity, keeping healthy stem cells safe and making the environment inhospitable for CH stem cells. The objective of this application is to define the mechanisms that switch the niche on and off, with the aim of blocking these mechanisms to make life hard for CH stem cells. The central hypothesis is that certain progeny of CH stem cells send signals to nearby blood vessel-lining cells in the niche to maintain the niche in an “on” configuration. Targetable signaling pathways can reduce the expansion of CH stem cells in the niche. We will complete two specific aims to test the hypothesis. Aim 1: Identify the upstream and downstream mediators(s) that normally turn off the niche and why this doesn't happen in CH. Aim 2: Determine the mechanism for turning on niche blood vessel-lining cells during stress in the presence of mutated cells. Both aims are well supported by preliminary studies and use methodologies that have already been established to be feasible. Our team has produced unique animal strains and models that allow, for the first time, genetic dissection of these processes and have developed novel ex vivo models of the niche and innovative single-cell sequencing technologies for molecular definition of the mechanisms at play. The research is innovative in its focus on how mutated blood stem cells and their progeny affect the niche under different physiologic states, challenging the view that niche functions are static and immutable. The significance of this work lies in identifying the molecular mechanisms that give malignant stem cells a competitive advantage in the niche and provides actionable therapeutic strategies to mitigate the risks for millions of people with CH. Project Number: 1R01HL175556-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Joseph Scandura | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $802,301 | Activity Code: R01 | Study Section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17555601A1