Discovering the genetic mutations that drive clonal hematopoiesis and myeloid malignancies, and understanding how these mutations contribute to malignant and non-malignant disease
Our laboratory has performed large-scale genetic studies of somatic mutations in myeloid malignancies to identify mutations that predict prognosis, response to therapy, and disease subtypes. (Ebert, et al. Nature 2008; Bejar, et al. NEJM 2011; Schneider, et al. Nat Med, 2016; Lindsley, et al. NEJM 2017) These studies aim to assist with the clinical management of patients with particular mutations, as well as to identify therapeutic targets for the treatment of myelodysplastic syndrome (MDS) and other myeloid malignancies.
Weeks and Ebert, Blood 2023
We have systematically examined the genetic landscape and clinical consequences of clonal hematopoiesis.
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Clonal Hematopoiesis of Indeterminate Potential (CHIP) increases the risk of lymphoid and myeloid malignancy, overall mortality, and the risk of therapy-related myeloid malignancies. Most strikingly, CHIP increases the risk of atherosclerotic cardiovascular disease and other inflammatory diseases. (Jaiswal, et al. NEJM 2014; Jaiswal, et al. NEJM 2017; Weeks, et al. NEJM Evidence 2023). Distinct patterns of somatic gene mutations and mosaic chromosomal alterations (mCAs) are associated with risk of lymphoid versus myeloid malignancies. (Niroula, et al. Nat Med 2021)
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Our laboratory has used genetic screens, murine models, and biochemical studies to identify and characterize genes that are central to the biology of myeloid malignancies and may be targetable lesions for the treatment of myeloid malignancies. (Puram, et al. Cell 2016; Boettcher, et al. Science 2019) As a guide for understanding aberrant differentiation in hematologic malignancies, we established a gene expression map of normal human hematopoiesis. (Novershtern, et al. Cell 2011) We also published the first use of CRISPR genome editing to create models of hematologic malignancies. (Heckl, et al. Nat Biotechnol 2014; Tothova et al., Cell Stem Cell 2017)