Project Term
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Project Summary
Clonal hematopoiesis (CH) often precedes AML development, yet the molecular basis of CH expansion and progression to AML remains a mystery. By deploying single-cell DNA methylation analysis of longitudinal human in-vitro and in-vivo CH models, I aim to identify DNA methylation defects promoting CH fitness advantage, specifically in response to chronic inflammation. This will facilitate the design of therapies to halt premalignant clonal expansions and ultimately prevent leukemic transformation.
Lay Abstract
Acute Myeloid Leukemia (AML) is an aggressive and hard-to-treat blood cancer that affects 125,000 people worldwide every year. AML often originates in two stages. In the first stage, a single blood stem cell acquires an epigenetic error that gives this cell a growth advantage, a process known as clonal hematopoiesis. This defective stem cell outgrows its healthy counterparts, and in a second stage, as it keeps on growing and accumulating additional errors in its DNA, ultimately leads to leukemia.
As we age, the levels of inflammatory molecules in our bodies increase. Inflammation is a risk factor for leukemia development, as it favors the growth of the defective stem cells carrying epigenetic errors. Epigenetic marks guide a cell on which parts of the DNA it should read – and which ones it shouldn’t, effectively providing the instructions to perform its function. However, it remains unclear why and how these epigenetic errors enable stem cells to thrive in an inflammatory environment.
This project aims to identify the specific epigenetic marks responsible for the first stages of aberrant stem cell expansion in clonal hematopoiesis, and to understand how these epigenetic defects help them overcome the detrimental effects of inflammation. My proposal leverages innovative technologies to analyze and engineer epigenetic modifications in human blood stem cells to study, for the first time, how specific epigenetic defects shift in single cells as they start to expand abnormally. I will also identify which epigenetic marks help these cells resist inflammation and disrupt their normal blood stem cell function.
If successful, this project will identify the specific set of epigenetic changes directly responsible for a growth advantage in hematopoietic stem cells, laying the ground for leukemia development. In the future, I will specifically investigate how these epigenetic changes continue to evolve over time to transform these cells into leukemia stem cells, cells with the full potential to drive and propagate acute myeloid leukemia. I will also deploy epigenetic inhibitors to revert the epigenetic changes that make stem cells grow abnormally. This research will benefit blood cancer patients by pinpointing specific molecular programs that could be detected and therapeutically targeted in the early stages of abnormal stem cell expansion preceding leukemia development, potentially preventing the disease from advancing to a difficult-to-treat stage.
Program
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