Growth Regulation and Therapy of Leukemias and Lymphomas

The overallgoal of this program project is to undertand the molecularmechanisms underlyingleukemia and lymphoma development and to devise novel therapeutic strategies to control lymphoid neoplasms. There are four highly interactive projects that progress from basic studies to clinicallyapplicable therapeutic strategies with a delicate balance between in vitro and in vivo model systems. Project 1: Cell Cycle Progression of Normal and Malignant 8 Cells: Dr. Snow willstudy the role of cell cycle regulators inthe ability of CD40 to synergise with 8CR to induce cell cycle progression in normal 8 cells. They willdetermine the basis of the diverse response patterns of three subgroups of8 cell lymphomas to CD40 signaling and the in vivo relevance of such CD40 signaling for 8 lymphoma growth uSing transgenic mice. Porject 2: Role of egr-1 gene in the growth regulation of normal 8 cells and 8 cell lymphoma: Dr. 80ndada willstudy the baais of 8 cell receptor induced down regulation of the immediate early gene, egr-1 and its relation to lymphoma growth inhibition using 8KS-2, a 8 cell lymphoma. The importance of egr-1 for 8 cell development and 8 lymphoma growth willbe studied in transgenic mice that express a dominant negative form of the egr-1 protein. Project 3: Biological characterization of human leukemic stem cells (LSC): Dr. Jordan willexamine the novel concept that LSC are the basis of relapse of drug treated leukemias. The growth requirement of LSC willbe characterized. Modulation of pro and anti-apoptotic genes willbe explored to control leukemic cell growth. Project 4: Graft-versus-tumor (GVT) activity of syngeneic/allogeneic graft versus host disease (GVHD): Dr. 8ryson willdetermine the cellular mechanisrns involved in GVHDand in GVT reaction. They will test the hypothesis that cyclosporin A induced oxidative stress directly participates in the induction of SGVHD. Cellular basis of the lack of memory in GVT responses willbe studied. Support for three Cores, a transgenic and genetically defined animal facility, histopathology and administrative core, is requested to support the rsearch in this P01 application.