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Member Information
Alan Gewirtz, MD
Professor, Internal Medicine and Pathology-Laboratory Medicine
Office Phone: 215-898-4499
Office Fax: 215-573-2078
Email: gewirtz@mail.med.upenn.edu
Website(s):
Education: MD 1976, State University of New York at Buffalo
Keywords: human megakaryocyte developmental biology, human hematopoietic cell development
Research and/or Clinical Interests:
The cell biology of normal and malignant human hematopoiesis.
Summary:
The long term interest of my laboratory has been the cell biology of normal and malignant human hematopoiesis, with an emphasis on clinically relevant problems. Within this broad theme, two distinct but nonetheless complementary areas of investigation have been pursued, each by a different working group within the laboratory.
One group works in the area of human megakaryocyte developmental biology. Our lab was one of the first to examine the growth characteristics of megakaryocyte progenitor cells in tissue culture in disorders of platelet production. These studies demonstrated the importance of ancillary marrow cells in regulating megakaryocytopoiesis and suggested that these assays have diagnostic and treatment related utility. My group was also one of the first to demonstrate the existence of autocrine type negative regulators of megakaryocyte development. More recently, using in situ hybridization, differential display, PCR, and other molecular techniques adapted for small cell numbers, we have studied more basic aspects of megakaryocyte development. We are particularly interested in the cell cycle events which regulate the development of polyploidy, and the relationship between endoreduplication and functional maturation.
Because it remains extremely difficult to obtain sufficient primary progenitor cells to study the molecular mechanisms which regulate hematopoietic cell growth, we developed a novel strategy to allow us to determine the function of a given gene in a small number of cells. Our approach was to disrupt gene function with antisense oligodeoxynucleotides (ODN) designed as reverse complements to the mRNA of interest. Using this technique, a second working group has examined the role of c-myb and other protooncogenes in human hematopoietic cell development. We have also seized upon the translational aspects of this methodology and have begun to develop antisense ODN as therapeutic agents. Using our basic studies as a guide for potential gene targets, we have demonstrated that malignant hematopoietic cells are more dependent on c-myb gene function than normal hematopoietic cells. These results prompted us to suggest that antisense oligos targeted to c-myb might prove useful as marrow purging agents. This hypothesis is currently being tested at Penn in the autologous transplant program. We also developed an in vivo model for testing these compounds, and these results form the underpinning for systemic trials.
Representative Publications:
DiPaola R.S., Kuczynski W.I., Onodera K., Ratajczak M.Z., Hijiya N., Moore J., and Gewirtz A.M. Evidence for a functional kit receptor in melanoma, breast, and lung carcinoma cells. Cancer Gene Therapy 4:176-182, 1997.
Ratajczak M.Z., Ratajczk J., Malica W., Pletcher, Jr C.H., Machalinski B., Moore J., Hsiao-ling Hung, and Gewirtz A.M. Recombinant Human Thrombopoietin (TPO) Stimulates Erythropoiesis by Inhibiting Erythyroid Progenitor Cell Apoptosis. Br.J. Haematol 98:8-17, 1997.
Ratajczak J., Woytek Marlicz M., Andrew Keidel A., Machalinski B., Ratajczak M.Z., and Gewirtz A.M. Effect of Interleukin-1 a and and Interleukin-1 b on Erythroid Progenitor Cell Growth in Serum Free Cultures: An in vitro study relevant to the pathogenesis of the anemia of chronic disease. Hematology 2:21-28, 1997.
