WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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The long-term goal of our research is to delineate the molecular events leading to bone marrow failure (BMF) and to identify new biomarkers for a more accurate diagnosis and a more specific treatment for patients with bone marrow failure. BMF is the diminished function of the bone marrow leading to inadequate blood cell production. BMF may affect all three major blood cell lineages (red blood cells, white blood cells, and platelets), although one lineage may be disproportionately affected. BMF is heterogeneous in its pathogenesis. Most cases of BMF are classified as idiopathic; relatively few cases are due to recognizable genetic diseases. Currently we are studying three BMF syndromes: Paroxysmal Nocturnal Hemoglobinuria (PNH), Dyskeratosis Congenita (DC), and Diamond Blackfan Anemia (DBA).

PNH is due to the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. PIGA is essential for the biosynthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. Blood cells from patients with PNH are therefore deficient in all GPI-anchored proteins. Our studies are to identify the growth/survival advantage that leads to the clonal expansion of mutant progenitor cells. We are interested in the mechanisms of thrombosis, which is the major cause of death in patients with PNH and we investigate the consequences caused by the lack of GPI-linked proteins on hematopoiesis, leukemogenesis, and immune response.

DC, in contrast to PNH, is inherited. Patients have in addition to bone marrow failure abnormalities of the skin, nails, and buccal mucosa. Patients with this disease have an increased risk to develop cancer. There is an X-linked, an autosomal recessive, and an autosomal dominant form of the disease, suggesting that several genes might be affected that participate in the same biological pathway. Patients with DC have excessively short telomeres. Our studies are to characterize the pathway of excessive telomere shortening in these patients and to understand the mechanisms that lead to bone marrow failure and cancer predisposition.

The most recent project in our laboratory is to study role of defective ribosomal biogenesis in the pathogenesis of red cell aplasia in patients with DBA. DBA is an inherited BMF syndrome, characterized by anemia, absence of red cell precursors in the bone marrow, growth retardation and other congenital anomalies, which vary. Mutations in the ribosomal protein RPS19 are found in about one fourth of DBA patients, suggesting that ribosomal biogenesis is altered in patients with this disease. Our studies are to characterize the defect(s) in ribosome biogenesis and to identify the pathways leading to red cell aplasia in patients with DBA.

Proposed model of the pathogenesis of bone marrow failure in patients with DC In this model excessively short telomeres are the underlying cause of clinical manifestations in patients with DC. Mutations in TERC or TERT affect the activity of telomerase. Mutations in DKC1 destabilize TERC and/or retard ribosome biogenesis. As telomeres get shorter there is an increase in genomic instability leading eventually to a cell crisis, cell cycle arrest, and cell death. Rare cells that can maintain telomere integrity emerge from the crisis as potentially malignant cells. From: Mason PJ, Wilson DB, Bessler M Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med 2005 Mar;5(2):159-70

Education

1981	Physician, Medical School of the University Zurich, Switzerland
1984	MD, University Basel, Switzerland
1994	PhD (medical genetics), University of London, UK

Post-graduate Training

1982	Resident in Clinical Pathology, Department of Pathology, Kantonspital St. Gallen, Teaching Hospital University Basel, Switzerland
1983	Research Fellow in Clinical Oncology, Department of Oncology, Kantonspital St. Gallen, Teaching Hospital University Basel, Switzerland
1984-1986	Resident, Department of Internal Medicine, Hospital Waid, University Zurich, Switzerland
1987-1988	Senior Resident, Department of Internal Medicine, Hospital Triemli, University Zurich, Switzerland
1988-1990	Fellow in Clinical Hematology, Department of Hematology, University Hospital Zurich, Switzerland
1990	Attending in Clinical Hematology, Hospital Waid, University Zurich, Switzerland
1990	Research Fellow in Clinical Genetics, Institute for Clinical Genetics, University Zurich, Switzerland
1991-1994	Research Fellow, Department of Hematology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK
1994-1997	Research Associate, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY

Academic Positions

1997-2003	Assistant Professor, Department of Medicine, Washington University School of Medicine, St. Louis, MO
1997-2003	Assistant Professor, Department of Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, MO
2003-2007	Associate Professor, Department of Medicine, Washington University School of Medicine, St. Louis, MO
2003-2007	Associate Professor, Department of Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, MO
2007-present	Professor, Department of Medicine, Washington University School of Medicine, St. Louis, MO
2007-present	Professor, Department of Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, MO

University & Hospital Appointments

Member, American Cancer Society/Institutional Research Grant Committe

Board Certification

	Internal Medicine/Hematology (Switzerland)
	Board Eligible:  Internal Medicine/Hematology

Honors & Awards

1990	Prize of the Swiss Society of Hematology
1991-1993	Fellowship of Walter Honegger Stiftung, Zurich
1991-1994	Overseas Research Students Award, UK
1991-1994	Weston Scholarship, London, UK
1993	Plenary Lecture at the Molecular Biology of Haematopoiesis, Basel
1995	Ellermann Prize
1998-2000	Junior Faculty Award, American Society of Hematology
2002-2005	Established Investigator of the American Heart Association
2002	Member of the American Society of Clinical Investigation
2003	Bursary Award from the Aplastic Anemia & Myelodysplastic Syndrome International Foundation
2004	Faculty Member, Hematology Faculty F1000 Medicine
2007	Member of the Association of American Physicians

Editorial Responsibilities

	Editorial Board, Blood
	Editorial Board, Clinical and Translational Science
	Faculty Member, Hematology Faculty, F1000 Medicine
	Scientific Subcommittee for Stem Cells, American Society of Hematology

Professional Societies

	American Society of Clinical Investigation
	American Society of Hematology
	European Society of Haematology
	British Genetic Society
	Swiss Society of Internal Medicine
	Swiss Society of Hematology
	Swiss Society of Medical Genetics

Updated: April 17, 2008