Richard L. Stevens, PhD
Professor, Department of Medicine, Harvard Medical School
Principal Investigator, Rheumatology, Immunology and Allergy, Brigham And Women's Hospital
DF/HCC Program AffiliationLeukemiaCancer Immunology
Mast cells release a diverse array of biologically active molecules (including cytokines, chemokines, leukotrienes, prostaglandins, amines, proteoglycans, and proteases) when these cells are activated through one of their surface receptors. Thus, these cells play a key role in inflammation. While it is well known that most allergic reactions are mast cell-dependent, the presence of increased numbers of mast cells in nearly all tumors suggests that these effector cells of the immune response also play prominent roles in cancer. Mast cells are a heterogeneous family of hematopoietic cells whose phenotype is dependent on the tissue microenvironment the mature cell eventually resides. In vitro and molecular biology approaches have been developed in this laboratory to identify the factors that regulate the differentiation and phenotypic properties of mouse and human mast cells. For example, by varying the culture conditions, bone marrow progenitor cells have been induced to differentiate and mature into populations of mast cells which differ in what mediators they express. A number of novel human and mouse mast cell-specific genes have been identified, and the transcripts are regulated as the mast cell's microenvironment is altered. For example, we identified a new cation-dependent, MC-restricted guanine exchange factor/phorbol ester receptor (designated as RasGRP4) that regulates MC development. This signaling protein controls what proteases and eicosanoids MCs eventually express. RasGRP1 is the first member of this family of signaling proteins, and dysregulation of RasGRP1 is the ninth leading cause virus-induced leukemia in mice. Preliminary data have suggested a role for RasGRP4 in mast cell leukemia and clear cell tumors of the kidney. The cis-acting elements and trans-acting DNA-binding proteins that regulate transcription of mast cell-specific genes are being identified, as well as the RNA-binding proteins that regulate the stability of their transcripts. At the genome level, how specific families of mast cell-specific protease genes are organized on chromosomes 14 and 17 are being investigated. Transgenic mice have been created that differ substantially in the number and phenotype of the mast cells that they have in their tissues. A novel adoptive transfer approach also has been developed to address the varied aspects of mast cell development and function in vivo. Lastly, what happens to a cancerous cell when it physcially interacts with a mast cell is being investigated.
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