APOPTOTIC AND CELL CYCLE GENES IN NEUROBLASTOMA

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DESCRIPTION: (adapted from the investigator's abstract) A subset of neuroblastoma tumors characterized by the loss of chromosome 1 band p36 and MYCN amplification are particularly aggressive and have a particularly bad prognosis. In addition, many of these tumors no longer respond to chemotherapeutic drugs, making their treatment very difficult. Studies from our lab, as well as others, have shown that a number of apoptotic genes are lost when the 1p36 region is deleted, but so far no corresponding mutations have been found in the remaining allele. However, the expression of several of these genes is either lost of substantially diminished, possibly by methylation. Furthermore, we have found that the FasR death pathway is inactivated and the cyclin D/CDK/INK/pRb pathway altered in the majority of these neuroblastomas. They hypothesize that abnormalities in apoptotic and cell cycle signaling pathways are necessary for the survival of neuroblastomas with amplified MYCN. We theorize that the inactivation of the FasR pathway in tumors with amplified MYCN may help to accommodate high levels of N-myc by allowing these cells to acquire resistance to cell death. In addition, the deletion of 1p36 may also contribute to the apoptotic signaling defect(s) in these cells. The abnormalities in the cyclin D/CDK/INK/pRb pathway may also reflect important cellular responses that are necessary to accommodate increased levels of N-myc. To test this hypothesis and to understand whether the disruption of apoptotic signaling and abnormal regulation of the cell cycle synergistically contribute to the progression of neuroblastoma with 1p36 loss and MYCN amplification they propose to do the following: (1) determine where the FasR pathway is blocked in neuroblastomas with MYCN amplification and 1p36 loss, and whether additional death pathways are affected; (2) determine why p16Ink4a does not function normally in these neuroblastomas; (3) determine whether neuroblastoma tumorigenesis requires the disruption of both apoptotic and cell cycle pathways.