Grant Challen, PhD

Aberrant epigenetic marks, such as DNA methylation and histone modification patterns, are widely reported in human hematopoietic malignancies, but the pathological consequences of these marks remain to be defined. Moreover, genetic mutations in a number of critical components of the epigenetic machinery have recently been discovered in diseases such as acute myeloid leukemia, myelodysplastic syndromes, and T-cell leukemia / lymphoma. There is mounting evidence for the importance of epigenetic mechanisms in the regulation of stem cell function. This area of study represents one of the next major fields of stem cell biology. As a post-doctoral fellow at Baylor College of Medicine, Grant identified a crucial role for the DNA methytransferase enzyme Dnmt3a in hematopoietic stem cell self-renewal versus differentiation fate decisions. 

In his independent research laboratory at Washington University in St. Louis, Grant has extended these studies into mouse models of hematopoietic transformation and shown that loss of Dnmt3a in the bone marrow leads to the development of myelodysplastic syndromes after long latency. The observation that hypomethylating agents such as decitabine can induce a clinical response in a subset of patients highlights the importance of targeting epigenetic marks in cancer therapy. However, cancers are driven by both global and specific epigenomic dysregulation and the key is to restore the abnormal marks while retaining the normal distribution. We are now developing molecular tools for locus-specific epigenomic remodeling. As a member of the Siteman Cancer Center, Dr. Challen is dedicated to a career in academic cancer research.