Epigenetic regulation (through DNA methylation, histone modifications, and chromatin remodeling) is an important component dictating HSC and progenitor cell fate decisions. In the hematopoietic system, many lineage-restricted promoters and enhancers are associated with specific, combinatorial histone modification patterns, which may determine their selective priming of gene expression during lineage commitment. We are using functional screening approaches, in vitro and in vivo, to identify key epigenetic regulators that drive lineage-commitment steps during early hematopoietic differentiation. Validated regulators will be pursued by complete in vivo characterization using mouse conditional knockout or overexpression models, and molecular characterization using ChIP-Seq, single-cell RNA-Seq, ATAC-Seq, bisulfite sequencing, and other emerging technologies to interrogate epigenetic changes within rare cell populations. In addition, we have begun to study how these mechanisms influence hematopoietic lineage commitment during aging.
The evolution of next-generation sequencing technologies has allowed unparalleled analytic depth of cancer genomes of individual patients, and has identified most (if not all) of the important mutations for a growing list of cancers. For those cancer types that have been sequenced, including human AML, the next step is to begin modeling and interpreting this data to develop improved, targeted therapies. In the case of AML, while recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, none of the current classification schemes are entirely accurate. This suggests that a more complete understanding of the genetic and epigenetic changes relevant to the pathogenesis of AML are required for better classification of risk and approaches to therapy. Notably, how the cell type-of-origin and the order of epigenetic changes or mutations alter leukemia phenotype and response to targeted therapy is completely unknown. We have devised and are currently utilizing novel in vitro- and in vivo-based modeling systems to accurately determine the impact of cell type-of-origin and depict the consequences of sequential acquisition of mutations driving human AML.
“Secondary” acute myeloid leukemia (sAML) arises in about one third of patients with myelodysplastic syndrome (MDS). sAML is generally resistant to traditional chemotherapy, and overall survival is universally poor. Two significant unmet needs in clinical management of MDS patients are: (1) reliably identifying patients at high risk of progressing to sAML, and (2) having effective therapeutic strategies in hand to prevent or delay progression to sAML. A lack of knowledge of the mechanisms underlying MDS-to-sAML progression has hindered efforts to develop more effective therapies. We are investigating how alterations in chromatin structure in the bone marrow of MDS patients contributes to genomic instability, and modeling recurrent mutations to define those responsible for progression of MDS to sAML. The goal of our studies is to identify specific mechanisms driving MDS-to-sAML progression, which will allow development of biomarkers to stratify patients at high risk and new therapies to prevent this progression.