WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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My major research interest is the molecular pathogenesis of acute myeloid leukemia (AML).

A number of recurring chromosomal translocations are observed in association with distinct subtypes of AML. These translocations are rare somatic mutations that occur in primitive hematopoietic cells. A fundamental unanswered question is: exactly what stage of hematopoietic development is targeted by these mutations? n addition, are these translocations sufficient for the development of leukemia, or are additional genetic events required? We have chosen transgenic mice as a model system to approach these questions. Our strategy is to express genes of interest in the pluripotent hematopoietic stem cell compartment of transgenic mice and ask whether any or all blood lineages are susceptible to transformation. This should allow us to define the transforming capability of a variety of leukemic oncoproteins. Furthermore, these mice will be valuable reagents for studying secondary and tertiary genetic events in the pathogenesis of leukemia and for the evaluation of novel therapies for AML.

One of the translocations we are interested is the t(8;21) which fuses the AML-1 and ETO genes. AML-1 is the DNA-binding component of the transcriptional activator, Core Binding Factor (CBF). One hypothesis is that AML-1/ETO may contribute to leukemogeneis by altering the function of CBF. No animal model of AML-1/ETO-induced leukemia has yet been developed. To perform these studies, we have focused on Sca-1, a gene that is highly expressed in the hematopoietic stem cells of C57BL/6 and 129/Sv mice. By creating targeted ("knock-in") mutations in the Sca-1 locus via homologous recombination in embryonic stem (ES) cells, we will be able to specifically express AML-1/ETO and other proteins of interest in the stem cell compartment of transgenic mice.

A parallel project involves an investigation of the normal biology of Sca-1, and other members of the highly conserved Ly-6 family of proteins. We have created a loss of function model for Sca-1. In characterizing the phenotype of Sca-1 deficient mice, we are focusing on the role of Sca-1 in regulating hematopoiesis and hematopoietic stem cell function.

Expression of EGFP is pancellular in clonal myeloid colonies derived from the bone marrow of Sca-1+/EGFP mice Bone marrow cells were sorted into Lin-EGFP+ (A-C), Lin-EGFP- (D-F), or Lin-Sca+ (G-I) populations and plated in methylcellulose. After 8 days of growth, colonies were examined by light (A,D,G) or fluorescence (B,E,H) microscopy. The same colonies viewed and photographed using these two techniques then were picked, stained with phycoerythrin-conjugated anti-Gr-1, and analyzed by flow cytometry (C,F,I). One representative colony is shown for each of the three sorted populations. Only CFU-GM were analyzed, as indicated by Gr-1 expression in all cases. The pattern of EGFP expression within a colony is pancellular, as indicated by uniform EGFP expression (B,H) or absence of EGFP expression (E). From: Hanson P, Mathews V, Marrus SH, Graubert TA Enhanced green fluorescent protein targeted to the Sca-1 (Ly-6A) locus in transgenic mice results in efficient marking of hematopoietic stem cells in vivo. Exp Hematol 2003 Feb;31(2):159-67

Education

1984	BA Biology and Philosophy (summa cum laude), Dartmouth College, Hanover, NH
1988	MD, Harvard University, Boston, MA

Post-graduate Training

1988-1989	Intern in Internal Medicine, Yale-New Haven Hospital, New Haven, CT
1989-1991	Resident in Internal Medicine, Yale-New Haven Hospital, New Haven CT
1991-1993	Research Fellow in Hematology, Yale School of Medicine, New Haven, CT
1993-1995	Fellow in Hematology-Oncology, Washington University School of Medicine, St. Louis, MO
1995-1999	Post-doctoral Research Associate, Washington University School of Medicine, St. Louis, MO

Academic Positions

1997-1999	Instructor, Department of Medicine, Washington University School of Medicine, St. Louis, MO
1999-present	Assistant Professor, Department of Medicine, Washington University School of Medicine, St. Louis, MO
1999-present	Assistant Professor, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
1999-present	Research Associate Member, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
2001-present	Director, High Speed Cell Sorter Core, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO

Appointments & Committees

2002-present	Organizer, Stem Cell Biology Group, Washington University School of Medicine
2003	Organizing Committee for Stem Cell Symposium, Washington University School of Medicine

Major Invited Professorships & Lectureships

2001	Stowers Institute, Kansas City, MO
2001	Raylor Medical School, Houston, TX
2003	Runx Meeting, Bolton Valley, VT

Professional Societies

1988-1990	American Medical Association
1992-present	American Society of Hematology
1993-1995	American College of Physicians

Board Certification

1991	Internal Medicine
1997	Medical Oncology

Honors & Awards

1984	Rufus Choate Scholar, Dartmouth College
1984	Phi Beta Kappa, Dartmouth College
1984-1988	Alfred K. Priest Fellowship
1985	Harvard Summer Research Award
2000	Faculty Scholar Award, American Society of Hematology
2001	Excellence in Mentoring Award, Washington University

Updated: November 23, 2005