MECHANISMS OF CLONAL DOMINANCE IN PNH

Johns Hopkins University, Baltimore MD

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Abstract

The principal investigator's immediate goal is to develop into a clinician/scientist capable of conducting independent basic research in the field of hematopoiesis. He is particularly interested in the study of bone marrow failure states, especially paroxysmal nocturnal hemoglobinuria (PNH). His long-term goal is to utilize his extensive laboratory and clinical training to develop novel and effective therapies for aplastic anemia, PNH and myelodysplasia. To accomplish these goals the PI will spend the majority of his time in the laboratory to uncover the molecular and cellular factors that contribute to PNH and other bone marrow failure states. He will also be involved with these patients in the clinic and develop novel therapeutic protocols based on his laboratory findings. Specifically, his laboratory research shows that the genetic defect in PNH (mutation of a gene termed PIG-A) confers a survival advantage to PNH cells by rendering them resistant to apoptotic death, similar to other anti-apoptotic oncogenes. The mechanism by which these cells acquire cellular resistance to apoptosis appears to result from insufficient quantities of the lipid ceramide. Based on his laboratory findings demonstrating that the biology of PNH is similar to other hematologic malignancies, i.e., inhibited apoptosis, he has begun treating PNH patients with cytotoxic chemotherapy. Preliminary results have demonstrated dramatic clinical improvement, and show this approach can induce a complete remission, even in end-stage patients. Understanding the mechanism of cellular resistance to apoptosis that results from PIG-A mutations will give greater insight into the clonal dominance observed in PNH and possibly other malignancies. Furthermore, these preclinical studies should lead to novel therapeutic approaches for PNH.