Gene-expression profiling of lymphoid malignancies: Identification of deregulated pathways and response prediction to therapy.

摘要

Gene expression profiling has great potential of (a) increasing our understanding of the pathogenesis of lymphoid malignancies and (b) as a tool for response-prediction to various lymphoma treatments. The following lymphomas with especially poorly understood pathogenesis were chosen for the profiling part of this project: Indolent Follicular Lymphomas that transformed to Diffuse Large B-cell Lymphoma (DLBCL), the blastic variant of Mantle Cell Lymphomas, and the two most distinct AIDS-related lymphomas, Burkitt Lymphoma and DLBCL-Immunoblastic Variant. RNA samples of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), who participated in a German clinical trial of the BCR/ABL tyrosine kinase inhibitor STI571, was used for a study aiming at predicting resistance to STI571.; The Affymetrix microarrays and various statistical analysis tools were used for profiling. Independent confirmation was obtained by quantitative RT-PCR and immunohistochemistry.; Novel candidate genes for a multistep lymphomagenesis have been identified and validated. These include ABL2, NEK2, PDCD-1, and VDUP1 in transformed FL. Several genes were identified in MCL-BV, which are involved in the cell cycle control at the G1/S and G2/M checkpoints or inhibit apoptotic cell death, suggesting a potential pathogenic role in the evolution of MCL-BV. The two most common ARL subtypes DLBCL-IBL and Burkitt lymphoma as well as non-AIDS DLBCL are clearly distinguished by distinct gene expression profiles. New candidate genes in the oncogenesis of ARL include C/EBP beta/NF-IL6, TACI, and HDAC1. The use of gene expression profiling demonstrated the clinical relevance of gene expression data for the pretreatment assessment of ALL patients. Ninety-five genes were identified whose expression could be used to predict sensitivity of leukemic cells to STI571. In addition, primary resistant leukemic cells expressed high levels of Bruton's tyrosine kinase and two ATP synthetases (ATP5A1 and ATP5C1), suggesting a role in the resistance mechanism.; In summary, these studies identified new target genes in a group of most aggressive lymphomas. In addition, the successful pretreatment response prediction in ALL demonstrates the clinical relevance of gene expression profiling.