We study the evolution of blood stem cells and how inflammation, metabolism, and environmental exposures determine which clones succeed. Our goal is to understand how changing these selective pressures can promote healthy hematopoiesis.

Blood formation is an evolutionary system. Throughout life, hematopoietic stem cells acquire mutations, but only some mutant clones gain a competitive advantage and expand. We study how selective pressures dictate which clones gain that advantage. We also ask whether they can be manipulated therapeutically to steer hematopoiesis toward health.

Our work focuses on clonal hematopoiesis and myeloproliferative neoplasms (MPNs). We do not study mutations such as JAK2V617F and TET2 in isolation. We study them within the environments where mutant and normal stem cells compete. We investigate how inflammation, metabolism, oxidative stress, diet, and other environmental exposures alter this competition and shape clonal evolution.

We also study how mutant clones reshape their own environment. Even a small population of mutant cells can produce inflammatory signals that alter much larger populations of genetically normal cells. We investigate how this communication between mutant and normal cells contributes to clonal expansion, stem-cell aging, inflammation, and cardiovascular disease.

Our long-term aim is to move from understanding clonal evolution to controlling it. We are identifying selective pressures that can be modified. From these we aim to develop strategies that preserve the fitness of normal stem cells, reduce the competitive advantage of mutant clones, and promote healthy hematopoiesis.

1. Evolution of Clonal Hematopoiesis & MPN

Why do mutant stem cells win?

The presence of a mutation alone does not determine whether a hematopoietic stem cell clone will expand. Its success depends on the environment in which it competes.

We study how inflammatory and metabolic stresses alter competition between normal hematopoietic stem cells and cells carrying mutations associated with clonal hematopoiesis and MPN. Mutant stem cells can respond differently to inflammatory signals than their normal counterparts, allowing them to maintain function under conditions that suppress normal hematopoiesis.

Our laboratory uses competitive transplantation, lineage tracing, stem-cell functional assays, molecular profiling, and mouse models to understand these differences in fitness. We are particularly interested in JAK2V617F and TET2, and in defining how chronic inflammation changes the balance between mutant and normal hematopoiesis.

This evolutionary perspective leads to a different therapeutic question: rather than asking only how can we kill the mutant clone?, we also ask how can we change the environment so that the mutant clone no longer has an advantage?

2. Inflammation, Metabolism & Cardiovascular Disease

How do mutant clones alter the health of normal cells and tissues?

Clonal hematopoiesis affects much more than the mutant cells themselves. People with clonal hematopoiesis have increased inflammatory and cardiovascular risk, even when the mutant clone represents only a minority of their blood cells.

We study how mutant hematopoietic cells communicate with and reprogram their genetically normal neighbors. A major focus is TET2-mutant clonal hematopoiesis and atherosclerosis.

Our work investigates how TET2 loss alters macrophage lipid handling, autophagy and lysosomal function, inflammasome activation, and inflammatory cytokine production. We are particularly interested in a bystander model in which abnormal lipid handling in TET2-mutant macrophages generates inflammatory signals that reprogram neighboring wild-type macrophages, increasing lipid uptake and foam-cell formation.

We are also investigating whether chronic exposure to inflammatory signals produced by mutant cells can impair normal hematopoietic stem cells, accelerating features of stem-cell aging and further shifting competition in favor of the mutant clone.

These studies address a fundamental question in clonal hematopoiesis: How can a relatively small mutant clone produce effects throughout an entire organism?

3. Changing the Selective Environment

Can we change the environment so that normal cells win?

Understanding the forces that drive clonal selection creates an opportunity to intervene before overt hematologic disease develops.

We study diet, oxidative stress, metabolism, and inflammatory signaling as potentially modifiable selective pressures. Our laboratory investigates dietary patterns and specific metabolic interventions in mouse models and translates promising approaches into human studies.

Our clinical and translational research includes nutritional interventions in patients with MPN and hematologic malignancies, as well as studies designed to understand how diet and other modifiable exposures influence inflammation, cardiovascular risk, and clonal behavior.

We are also investigating approaches that target reactive oxygen species and cellular stress, including strategies that distinguish cytosolic from mitochondrial oxidative stress and determine how each influences normal and mutant stem-cell fitness.

The long-term goal is a new approach to prevention and treatment: rather than waiting for a mutant clone to progress, we want to determine whether we can reshape the selective environment early enough to prevent progression and its systemic consequences.

From Mechanism to Patients

Our research moves iteratively between hematopoietic stem-cell biology, mouse models, primary human samples, and clinical intervention studies. Observations in patients generate mechanistic questions in the laboratory, while discoveries in experimental models inform interventions that can be tested in people.

Across these studies, one question connects our work:

Can we understand the rules governing clonal evolution well enough to change them?

Our goal is to translate those rules into strategies that protect normal hematopoiesis, control mutant clonal expansion, and prevent the inflammatory and cardiovascular consequences of clonal hematopoiesis and MPN.