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
RESEARCH INTERESTS - Cancer Predisposition Mechanisms; Epigenetics; Hematology; Genomics/Precision Medicine; Stem/Progenitor Cell Biology
B.S., 1984, University of Vermont, Burlington, VT, Biochemistry (honors)
B.A., 1984, University of Vermont, Burlington, VT, Anthropology
Ph.D., 1989, University of Michigan, Ann Arbor, MI, Pharmacology (with William B. Pratt)
Postdoctoral Research, National Institutes of Health (with Gordon Hager and Gary Felsenfeld)
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 and differentiation.
- Johnson et al. (2020) Constructing and deconstructing GATA2-dependent cell fate programs to establish developmental trajectories. J. Exp. Med., in press
- Liao et al. (2020) Discovering how heme controls genome function through heme-omics. Cell Rep.
- Cavalante de Andrade et al. Breaking the spatial constraint between neighboring zinc fingers: a new germline mutation in GATA2 deficiency syndrome. Leukemia.
- Churpek et al. (2019) Transcription factor mutations as a cause of myeloid neoplasms. J. Clin. Invest.
- Soukup et al. (2019) Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer. J. Clin. Invest.
- Katsumura et al. (2018) Human leukemia mutations corrupt but do not abrogate GATA2 function. Proc. Natl. Acad. Sci.
- Tanimura et al. (2018) GATA/heme multi-omics reveals a trace metal-dependent cellular differentiation mechanism. Dev. Cell.
- Mehta et al. (2017) Integrating enhancer mechanisms to establish a hierarchical blood development program. Cell Rep.
- Hewitt et al. (2017) GATA factor-regulated Samd14 enhancer confers red blood cell regeneration and survival in severe anemia. Dev Cell.
- Johnson et al. (2015) Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Advances.
- Hewitt et al. (2015) Hematopoietic signaling mechanism revealed from a stem/progenitor cell cistrome. Mol. Cell.