Project Term
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Project Summary
Clonal cytopenia of undetermined significance (CCUS) is a poorly understood precursor condition linking clonal hematopoiesis with myeloid malignancy. Motivated by human biobank data, I developed a novel murine model of neutropenic CCUS and found interleukin-17A to be necessary and sufficient to propel Tet2-deficient clonal outgrowth. The objectives of this project are to define the drivers of interleukin-17A liberation in neutropenic CCUS and the mechanism by which it hastens clonal progression.
Lay Abstract
Clonal hematopoiesis arises when mutations arise in blood-forming stem cells as we age. These mutations can make affected people more likely to subsequently develop blood cancers. Scientists and physicians have dedicated considerable effort toward finding features that indicate which people with clonal hematopoiesis will develop blood cancers and which will not. Among the strongest predictors for poor outcomes is dropping blood counts, including reduced numbers of neutrophils (the white blood cells that help fight infections). It is unknown whether low neutrophil count (neutropenia) is simply a symptom of dysfunctional blood formation or if it contributes to the progression of disease. To address this question, I developed a new series of mouse models that combine competitive clonal hematopoiesis with the ability to durably remove neutrophils from the blood. In preliminary experiments, I found that low neutrophil counts preferentially drive expansion of blood stem cells lacking the Tet2 gene, which is commonly mutated in patients with clonal hematopoiesis. I found that this expansion is associated with increased levels of inflammatory proteins in the blood (called cytokines) that have been previously implicated in regulating blood cell production. Blocking the function of one of these cytokines appears to halt the accelerated disease progression when neutrophil counts are low. These findings led me to predict that the liberation of this cytokine is the driving the disease progression seen with neutropenia. This project seeks to understand: (i) Where this cytokine is originating from in neutropenic animals and what signals are regulating its release, and (ii) How this cytokine is driving blood-forming stem cells lacking Tet2 to proliferate and expand disproportionately. Obtaining a mechanistic understanding of this systemic response to neutropenia in clonal hematopoiesis, if successful, will provide at least two benefits to patients with clonal hematopoiesis and related blood cancers: (i) It will motivate human-based studies to determine whether blood levels of this cytokine can serve as a powerful predictive biomarker for those at high risk of developing future blood cancer, and (ii) It may provide a new target for medicines designed to block the cytokine and potentially slow progression toward blood cancer.
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