WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

• Questions or comments
• Search

We are studying the role of the perforin/granzyme pathway for the functions of both cytotoxic lymphocytes (CD8 and natural killer cells) and regulatory T cells using in vivo models of Graft vs. Host Disease, viral clearance, and tumor clearance. We have recently learned that granzyme B plays an important role in the ability of regulatory T cells to suppress NK cell function in tumor clearance models. Further, we are using proteomic approaches to define the critical substrates that granzymes A, B, and C cleave to initiate cell death. Each protease has a unique set of non-overlapping substrates that are critical for either initiating apoptosis and/or promoting cellular integrity.

Our laboratory also studies the pathogenesis of acute myeloid leukemia, using both genetic and genomic approaches. We have built several mouse models of acute promyelocytic leukemia (APL) by expressing the PML-RARA fusion gene (created by a translocation that occurs in nearly all human APL patients) in the early myeloid cells of mice. These mice recapitulate many features of the human disease, and have been valuable reagents for dissecting the genetic pathways altered by PML-RARA. Further, in collaboration with the Washington University Genome Sequencing Center, our group has been actively engaged in identifying the mutations responsible for the initiation and progression of acute myeloid leukemia. We have used array-based genomic screens (comparative genomic hybridization, SNP genotyping, and expression profiling) to identify candidate genes for resequencing, and have now identified a number of novel somatic mutations in AML cell genomes for further validation and study.

Finally, our laboratory has long been interested in homologous recombination as a tool for correcting single gene defects. We are using both genetic approaches and expression profiling to identify the homologous recombination "signature" to improve the efficiency of this process in both embryonic and hematopoietic stem cells.

Model for the interaction of neutrophil elastase and PML-RAR in mouse models of APL Neutrophil elastase protein production (green curve) is maximal in the promyelocyte compartment of myeloid maturation. MRP8, CG, and retroviral driven mouse models of APL (red) all direct expression of PML-RAR to the promyelocyte compartment, where NE is produced; all result in APL. The retrovirally driven model causes PML-RAR to be expressed outside of the promyelocytic compartment and in other hematopoietic lineages, but the only leukemia that develops in these mice is APL. CD11b (blue) drives PML-RAR expression after NE expression occurs and does not cause APL. From: Lane AA, Ley TJ Neutrophil elastase cleaves PML-RARalpha and is important for the development of acute promyelocytic leukemia in mice. Cell 2003 Oct 31;115(3):305-18

Education

1974	BA, Drake University, Des Moines, IA
1978	MD, Washington University School of Medicine, St. Louis, MO

Post-graduate Training

1978-1979	Intern in Medicine, Massachusetts General Hospital, Boston, MA
1979-1980	Assistant Resident in Medicine, Massachusetts General Hospital, Boston, MA
1980-1983	Clinical Associate, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
1983-1984	Hematology-Oncology Fellow, Washington University Medical Center, St. Louis, MO

Academic Positions & Employment

1984-1986	Senior Investigator, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
1986-1990	Assistant Professor of Medicine, Washington University School of Medicine, St. Louis, MO
1986-1993	Assistant Professor of Genetics, Washington University School of Medicine, St. Louis, MO
1990-1993	Associate Professor of Medicine, Washington University School of Medicine, St. Louis, MO
1993-present	Professor of Medicine, Washington University School of Medicine, St. Louis, MO
1993-present	Professor of Genetics, Washington University School of Medicine, St. Louis, MO
1994-2000	Director, Hematopoiesis Research Center, Washington University School of Medicine, St. Louis, MO
2000-present	Director, Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, St. Louis, MO
2000-present	Associate Director for Basic Science, Alvin J. Siteman Cancer Center, Washington University, St. Louis, MO

Board Certification

1981	American Board of Internal Medicine
1984	American Board of Internal Medicine (Hematology

Professional Societies

	Alpha Omega Alpha
	American Society of Hematology
	American Association for the Advancement of Science
	American Society for Biochemistry and Molecular Biology
	American Society for Clinical Investigation
	Association of American Physicians

Honors & Awards

1974	Phi Beta Kappa, Drake University, Des Moines, IA
1974	Ross Award for Promise of Success in Medicine, Drake University
1974	Phi Eta Sigma Award (Best Academic Record), Drake University
1975	E.V. Cowdry Prize in Histology, Washington University, St. Louis, MO
1976	Robert Carter Medical School Prize, Washington University, St. Louis, MO
1978	Alpha Omega Alpha
1978	St. Louis Internists Club Book Prize (For Achievement in Medicine), Washington University, St. Louis, MO
1978	Medical Fund Society Prize in Surgery, Washington University, St. Louis, MO
1978	Alpha Omega Alpha Book Prize (Best Academic Record), Washington University, St. Louis, MO
1986-1988	Basil O'Conner Scholar, March of Dimes Foundation
1990	Elected, American Society for Clinical Investigation
1994	Teacher of the Year, Dept. of Medicine, Jewish Hospital
1995	Elected, Association of American Physicians
1998	Alumni-Faculty Award, Washington University Medical School
1999	Alan A. & Edith L. Wolff Professorship in Medicine
1999	MERIT Award, National Institutes of Health
2000	ASCI Special Service Award
2000	Internal Medicine Leadership Award in Scientific Investigation, Washington University Medical School
2001	St. Louis Spirit of Health Award, American Cancer Society
2001	Excellence in Teaching and Mentoring, Markey Special Emphasis Pathway, Washington University Medical School
2002	Elected, Fellow of AAAS (American Association for the Advancement of Science)
2003	Member, Institute of Medicine, National Academy of Sciences
2004	Special Recognition, Outstanding Faculty Mentor Award, Washington University Medical School
2005	Herman Beerman Award, Society of Investigative Dermatology
2005	America's Top Physicians, Consumers' Research Council of America
2007	Fellow, St. Louis Academy of Science
2007-2011	AAP Council Member
2007	Best Doctors in America
2008	Distinguished Educator Award for Postdoctoral Mentoring, Washington University Medical School

National Leadership Positions, Societies, & Boards

1990-1991	Chairman, Committee on Scientific Affairs, American Society of Hematology
1992-present	Cooley's Anemia Foundation Medical Advisory Board
1993	President, National Blood Club
1992-1996	Hematology I Study Section, ad hoc member
1997-1998	President, American Society for Clinical Investigation
1998-2001	FASEB Board of Directors
2004-2005	General Motors Foundation, Awards Committee
2004-2007	American Society of Hematology, Awards Committee
2007-present	International Cancer Genomics Consortium Scientific Planning Committee
2008-2011	Treasurer, Association of American Physicians
2008-2012	NHGRI Board of Scientific Counselors

Editorial Boards

1990-1996 1998-2003	Blood
1995-1998	Clinical Molecular Pathology
1998-2003	Journal of Clinical Investigation

Updated: April 1, 2008