Position title: Gary Felsenfeld Professor of Cell and Regenerative Biology; Lowell and Gwendolyn Smythe Endowed Professor, Director, UW-Madison Blood Cancer Research Program
Phone: (608) 265-6446
1111 Highland Ave
Madison, WI 53705
- Bresnick Lab
PhD, Pharmacology, The University of Michigan Medical School
Postdoctoral, National Institutes of Health, Laboratory of Molecular Biology
Cancer predisposition mechanisms; epigenetics; hematology; genomics/precision medicine; stem/progenitor cell biology
Dr. Bresnick’s group discovered genetic mechanisms that govern development of the hematopoietic system. Transcriptional enhancers operating in these mechanisms are essential for hematopoiesis in humans and mice, embryonic development, and their disruption causes cancer and other blood diseases. Mechanistic studies unveiled new paradigms to explain hematopoietic stem cell generation, myeloid progenitor cell fate decisions and erythrocyte development. Aberrations in GATA2 expression resulting from germline mutation of one of these enhancers (+9.5) (or coding region mutations) cause “GATA2-deficiency syndrome”, which involves immunodeficiency, bone marrow failure and predisposition to develop myelodysplastic syndromes and acute myeloid leukemia. An additional enhancer discovered by the Bresnick group (-77) is expropriated by the leukemogenic protooncogene EVI1, thus defining a novel leukemogenic paradigm. Clinical centers screen for genetic variation in these enhancers to diagnose the etiology of blood diseases.
A major focus involves multi-disciplinary studies of pre-malignant states. We have identified GATA2-instigated genetic and protein networks that control hematopoiesis and are deciphering the importance of network components and how they function as integrated units in physiology and pathology. The network components include potential targets to improve the diagnosis, treatment and prevention of blood diseases. We are testing the mechanistic and pathological consequences of dysregulating network components. Innovative screening systems have been developed to forge strategies to rescue defective networks, thus overcoming differentiation blockades that underlie leukemia and cytopenias.
Another uses multiomics (quantitative proteomic, transcriptomic, metabolomic and metallomic) with cell populations and single cells to understand myeloid and erythroid cell development and function in physiology, stress and disease. Of note are discoveries of GATA factor links to innate immune mechanisms, epigenetic mechanisms underlying cellular differentiation, heme as a determinant of genome function, RNA-regulatory exosome complex requirement to balance progenitor cell proliferation and differentiation and trace metal mechanisms that control cell survival.