Christopher H. Lowrey, M.D.
Professor of Medicine
Professor of Pharmacology & Toxicology
Chief, Division of Hematology
Vice Chair, Department of Medicine
Pharmacology & Toxicology
Boston University School of Medicine, MD 1985
University of Pennsylvania, MA 1981
Bowdoin College, BA 1979
Norris Cotton Cancer Center
Pharmacology and Toxicology Graduate Program
Program in Experimental and Molecular Medicine
Christopher H. Lowrey, MD
Section of Hematology/Oncology
Dartmouth-Hitchcock Medical Center
Lebanon NH 03756
Research Description: Role of epigenetics and cell stress signaling in normal and disease-related blood cell production; development of novel pharmacologic therapies for sickle cell disease, thalassemia and leukemia.
Our lab is primarily focused on developing therapies for sickle cell disease and beta-thalassemia by targeting underlying molecular mechanisms. These diseases (termed hemoglobinopathies), along with the alpha thalassemias, affect more people world-wide than any other class of genetic disease. While patients with access to modern medical care live into middle age, they must often deal with severe side effects. People with these diseases who do not have access to modern medical care often do not live beyond early childhood. These diseases result from mutations affecting the human beta-globin gene. It turns out that humans have a perfectly good substitute genes (the two gamma-globin genes) that are normally only expressed during fetal development. Proof of principle studies have shown that if these genes can be turned on in adult patients then their conditions can be dramatically improved. Unfortunately, all currently available drugs that activate the fetal globin genes lack the effectiveness, safety profile and ease of use that would make them applicable to most people with these diseases. In our lab we are studying the mechanisms by which the fetal globin genes are silenced following birth and how known inducers of the genes work to reactivate their expression. Our work includes studying the role of DNA methylation and histone modification (epigenetics) and the role of cell signaling in these processes. By identifying key pathways and regulatory molecules we are developing novel targeted pharmacologic agents for fetal hemoglobin induction that will be safe and effective so that they can be used to treat patients throughout the world.
Medical Pharmacology (Cancer Chemotherapy) - DMS 2
Scientific Basis of Medicine (Hematology) - DMS 2
Program in Experimental and Molecular Medicine (long-range chromatin structure, leukemia)
Clinical Experience in Hematolgy and Bone Marrow Transplant - DMS4
Dr. Lowrey received his BA in Biochemistry from Bowdoin College in 1979 and his MA, also in Biochemistry, from the University of Pennsylvania in 1982. He received his MD from Boston University School of Medicine in 1985 and subsequently performed his residency in internal medicine at Tufts New England Medical Center in Boston and at the National Institutes of Health Clinical Center in Bethesda, MD. He then served as a Medical Staff Fellow and Senior Staff Fellow in the Clinical Hematology Branch of the National Heart, Lung, and Blood Institute of N.I.H. where he completed his fellowship in Hematology in 1992. In 1993 he joined the faculty of Dartmouth Medical School where he holds a joint appointment in the Departments of Medicine and Pharmacology.
Induction of fetal hemoglobin through enhanced translation efficiency of γ-globin mRNA.
Multiple physical stresses induce γ-globin gene expression and fetal hemoglobin production in erythroid cells.
Laboratory tests for paroxysmal nocturnal hemoglobinuria.
Vinblastine rapidly induces NOXA and acutely sensitizes primary chronic lymphocytic leukemia cells to ABT-737.
Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism.
Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells.
Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis.
Novel therapeutic candidates, identified by molecular modeling, induce γ-globin gene expression in vivo.
Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway.
Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed.