By producing over 2 million of new mature blood cells every second, the bone marrow, which is the home of the hematopoietic system, is the hardest working organ in the human body. Many specialized genes must be turned on and off in a highly coordinated manner to maintain normal function of the hematopoietic stem cells (HSCs) while ensuring replenishment of multiple differentiated cell types. In the Guryanova lab, we study the epigenetic (or gene regulation) mechanisms that sustain life-long blood production and what can go awry leading to pre-malignant changes in the HSCs and ultimately to acute myeloid leukemia (AML). We use this mechanistic knowledge to develop better therapies and improve the lives of leukemia patients.
We recently discovered that leukemia cells with a mutation in DNMT3A, a critical epigenetic modifier gene often altered in blood malignancies, are sensitive to pharmacologically-induced replication fork stalling due to a functional defect in PARP-dependent DNA damage repair mechanism, with translational implications. Next, in an effort to identify the molecular drivers of pre-malignant clonal evolution in the blood system, we developed a genetic lineage tracing mouse model that enabled us to pinpoint gene signatures and signaling nodes enriched in “winner” and “loser” hematopoietic clones and to characterize their epigenetic states. Finally, we are investigating how mutations in the blood system contribute to disease conditions in other tissues such as aggressive colorectal cancer.
• Normal, Premalignant, and Leukemic Hematopoiesis
• Cancer Epigenetics
• Clonal Evolution of Hematopoiesis
• Acute Myeloid Leukemia (AML)
• Novel Therapeutic Approaches for Leukemia
• Clonal Hematopoiesis and Cross-Talk with Other Tissues
• Innocatice clinically-accurate genetic mouse models
• Flow cytometry and Fluorescence-Activated Cell Sorting (FACS)
• Next generation-based gene expression, epigenetic , and chromatin accessibility profiling
• Pre-clinical therapeutic studies in vivo
• In vivo lineage tracing
• Hematopoietic stem and progenitor cell assays
Check out the recent publications from the Primary Investigator (PI), Dr. Olga Guryanova