Frederick W. Alt, PhD
Charles A. Janeway Professor of Pediatrics, Department of Pediatrics, Harvard Medical School
Professor, Department of Genetics, Harvard Medical School
Investigator, Howard Hughes Medical Institute, Boston Children's Hospital
DF/HCC Program AffiliationLymphoma and MyelomaCancer Immunology
The broad focus of the Alt laboratory is the elucidation of mechanisms involved in maintenance of genomic stability in mammalian cells. More specifically, the laboratory studies the mechanism and control of antigen receptor variable region gene assembly (VDJ recombination) in developing B and T lymphocytes and the mechanism of immunoglobulin heavy chain class switch recombination (CSR) and somatic hypermutation in activated mature B lymphocytes. Studies of the regulation of these processes involve elucidation of signaling events that lead to their activation, as well as elucidation of cis-acting chromosomal processes that effect accessibility of antigen receptor genes to lymphocyte specific DNA modification enzymes (i.e. RAG endonuclease and Activation Induced Deaminase). Mechanistic studies focus on the role of various, general DNA repair pathways in completing these lymphocyte-specific genetic alterations and in biochemical studies aimed at elucidating the molecular mechanisms by which Activation Induced Deaminase functions in somatic hypermutation and CSR and how the DNA damage response is involved in the completing the CSR reaction. The laboratory also studies how defects in VDJ recombination and CSR can lead to translocations associated with lymphoid malignancies. In this regard, a major current focus of the laboratory is the elucidation mechanisms by which the interplay of DNA repair and cell cycle checkpoint mechanisms acts to suppress genomic instability, lymphomas, and solid tumors. Laboratory approaches range from basic molecular genetics, biochemistry, proteomics, and genomics to gene-targeted mutation and the generation of novel animal-based approaches and models.
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