|
Research Summary
Human globin gene regulation and gene therapy
Research Activities
The regulation of human globin gene expression is complex, and mediated by both cis-acting DNA sequences within and surrounding the globin genes, and by transacting factors differentially active in fetal and adult hematopoietic cells. Our goal is to understand how this process works and to manipulate it to provide new approaches to the treatment of inherited anemias such as sickle cell disease and beta thalassemia. Recently, we have defined a unique chromatin remodeling complex (PYR complex) that uses the transcription factor, Ikaros, as its DNA binding subunit. PYR complex is present only in adult hematopoietic cells, and deletion of its DNA-binding site between the human fetal and adult globin genes delays switching in transgenic mice. We are also analyzing the structure and function of PYR complex in different hematopoietic cell lineages.
Retroviral and lentiviral gene transfer provide approaches to the potential cure of patients with disorders of human hemoglobin. Efficient gene transfer and high level expression of human beta or gamma globin genes into human hematopoietic stem cells (HSC) could accomplish this goal. We are already using methods to: (1) isolate human HSC; (2) grow these HSC ex vivo;(3) transduce HSC with new genes; and (4) select and enrich for those HSC into which such genes have been transferred. We are trying to optimize this system by constructing new defective retroviruses and lentiviruses, and establishing conditions that permit human HSC from patients to be suitably engineered to express normal amounts of human beta or gamma globin genes, and then re-administering the engineered cells as therapy.
Positions & Appointments
| 1980-present |
Director - Division of Hematology, Department of Medicine |
College of Physicians and Surgeons, Columbia University |
New York, NY |
| 1975-present |
Professor - Department of Medicine, and Department of Genetics & Development |
College of Physicians and Surgeons, Columbia University |
New York, NY |
| 1975-present |
Attending Physician |
College of Physicians and Surgeons, Columbia University |
New York, NY |
| 1970-1993 |
Director - Department of Clinical Pathology |
Columbia-Presbyterian Medical Center |
New York, NY |
| 1984-1988 |
Adjunct Professor - Department of Cell Biology and Anatomy |
Graduate School of Medical Sciences, Cornell University |
New York, NY |
Education and Training
| 1956 |
A.B. |
Columbia University, New York, NY |
| 1960 |
M.D. |
Harvard University Medical School, Cambridge, MA |
Honors and Awards
1966-1971 Leukemia Society Scholar
1970 Traveling Fellowship, Royal Society of Medicine
1971-1976 Faculty Research Award, American Cancer Society
1984 Rachford Lecturer, University of Cincinnati
1984 Dean's Distinguished Lecturer, College of Physicians and Surgeons, Columbia University
1985 Keynote Address, Twenty-fifth Alumni Reunion, Harvard Medical School
1988 Mark Falcon Lesses Visiting Professor, Harvard Medical School/Beth Israel Hospital
1988-1996 MERIT Award from the National Institute of Diabetes and Digestive and Kidney Diseases
1996 AAAS Fellow, American Association for the Advancement of Science
1997 First Recipient of the Eagle and Rose Medal for Medical Research, Cooley's Anemia Foundation
2000 Izak Memorial Lecture, Hadassah University, Jerusalem, Israel
Committees and Society Memberships
Fellow of the American College of Physicians
Diplomate of the American Board of Internal Medicine
American Society of Hematology
Association of American Physicians
American Society for Clinical Investigation
American Federation for Medical Research
Fellow of the Molecular Medicine Society
American Society of Biological Chemists
Harvey Society
Society for the Study of Blood
New York Academy of Sciences
American Association for the Advancement of Science
American Association for Cancer Research
American Society of Human Genetics
Association of Hematology and Oncology Program Directors
American Society for Biochemistry and Molecular Biology
New York State Society of Medical Oncologists and Hematologists
Association of Subspecialty Professors
American Society of Gene Therapy
International Society for Experimental Hematology
American Society of Clinical Oncology
Special Interests
1) Regulation of human hemoglobin gene expression. Molecular events controlling the switch from fetal to adult hemoglobin production; and 2) Gene Therapy. Transfer and expression of genes into peripheral blood and bone marrow stem cells. MDR and globin genes as targets for gene therapy.
I am a physician-scientist who makes rounds, teaches, and does research. My laboratory is interested in human globin gene regulation and hematopoietic stem cell gene therapy. We are currently working on the role of a chromatin remodeling complex in human fetal to adult globin switching, and transferring and expressing the human B globin gene and drug resistance genes into hematopoietic stem cells.
Selected Publications:
1. Lopez, R.A., Schoetz, S., DeAngelis, K., O'Neill, D., and Bank, A. (2002) Multiiple hematopoietic defects and delayed globin switching in Ikaros-null mice. Proc. Natl. Acad.Sci.
99:602-607
2. Abonour R, Williams DA, Einhorn L, Hall KM, Chen J, Coffman J, Traycoff CM, Bank A, Kato I, Ward M, Williams SD, Hromas R, Robertson MJ, Smith FO, Woo D, Mills B, Srour EF, and Cornetta K. (2000) Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells. Nature Med.
6:652-658
3. O'Neill D, Schoetz SS, Lopez RA, Castle M, Rabinowitz L, Shor E, Krawchuk D, Goll MG, Renz M, Seelig HP, Han S, Seong RH, Park SD, Agalioti T, Munshi N, Thanos D, Erdjument-Bromage H, Tempst P, and Bank A. (2000) An Ikaros-containing chromatin remodeling complex in adult-type erythroid cells. Mol Cell Biol.
20:7572-7582
4. O'Neill D, Yang J, Erdjument-Bromage H, Bornschlegel K, Tempst K, and Bank A. (1999) Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching. Proc Natl Acad Sci USA
96:349-354
5. Ward M, Pioli P, Ayello J, Urzi G, Richardson C, Hesdorffer C, and Bank A. (1996) Retroviral transfer and expression of the human multiple drug resistance gene in peripheral blood progenitor cells. Clin Cancer Res
2:873-876
6. Ward M, Richardson C, Pioli P, Smith L, Podda S, Goff S, Hesdorffer C, and Bank A. (1994) Transfer and expression of the human multiple drug (MDR) gene in human CD34+ cells. Blood
84:1408-1414
|
