Immunology Graduate Group
Martin Carroll, M.D.
Assistant Professor,
Medicine/Hematology-Oncology
Address: BRB 2/3, Rm. 708, 421 Curie Blvd., Philadelphia, PA 19104
Office Phone: (215) 573-5217
Lab Phone: (215) 573-3385
Fax: (215) 573-7049
Email: carroll2@mail.med.upenn.edu
Education:
M.D., Dartmouth Medical School
A.B., Harvard College
Research Interests
Signal transduction in leukemia, genomic instability in leukemia
Research Summary
Our laboratory is interested in the molecular signal transduction events that lead to the development of chronic and acute myeloid leukemia. There are two active areas of research in the lab.
The Role of BCR/ABL in genomic instability: The BCR/ABL protein has clearly been shown to lead to the proliferative events associated with chronic phase in CML, however whether BCR/ABL is responsible for blast crisis is unclear. We have recently demonstrated that after genotoxic stress, BCR/ABL translocates to the nucleus and associates with the ataxia-telangiectasia mutant (ATM) protein, leading to a delay in DNA repair. Furthermore, BCR/ABL disrupts an intra-S phase checkpoint leading to a radioresistant DNA synthesis phenotype (RDS). The mechanism of this action is through disruption of ATR dependent signaling pathways. Experiments are underway to if BCR/ABL induces gross chromosomal rearrangements (GCR) and whether BCR/ABL disrupts ATR signaling after other types of physiologic stress.
Signal transduction in AML: Although many fusion proteins have been identified with AML, most of these proteins are transcription factor proteins which probably function to block differentiation. Very little is known about the regulation of cell growth in AML however. There are several technical reasons why this is so and we have been working to resolve these. Patient's cells are now brought back to the lab and studied for their growth in tissue culture conditions. We have shown that several signaling pathways are activated in these cells including STAT5, a MAP kinase known as p38 and PI3 kinase. We want to continue to characterize these signaling pathways. In particular, we are interested in using pharmacologic inhibitors of signaling pathways and expression of dominant negative proteins to study their effects on growth of the AML cells. The goal of this project is to develop signal transduction inhibitors for use in the treatment of AML. There are several areas here that are wide open for investigation including investigation of culture techniques both in vitro and using NOD/SCID animals, further development of the technology to analyze signaling in primary cells, studies of the effects of inhibiting signaling pathways in various models.
Recent Publications
1. Xu, Q., Simpson S, Scialla T, Bagg A., Carroll M. (2003) Survival of Acute Myeloid Leukemic Cells Requires PI3 Kinase Activation, Blood, 102(3):972-80.
2. Dierov J, Dierova R, Carroll, M (2003) BCR/ABL Translocates to the Nucleus After DNA Damage and Disrupts an ATR Dependent Cell Cycle Checkpoint. Submitted.