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Abstract

Abstract 

  1. Somatically acquired chromosomal translocations activate proto-oncogenes in the hematopoietic cells of both children and adults. This mechanism of gene dysregulation contributes to well over 50 percent of all leukemias that have been characterized cytogenetically and molecularly and to a substantial proportion of lymphomas, notably the Burkitt, large-cell, and follicular types.

  2. In most instances, chromosomal translocations fuse sequences of a transcription factor or receptor tyrosine kinase gene to those of a normally unrelated gene, resulting in a chimeric protein with oncogenic properties. Repositioning of transcriptional control genes to the vicinity of highly active promoter/enhancer elements, such as those associated with immunoglobulin or T-cell receptor genes, is a second mechanism by which chromosomal translocations induce malignancy.

  3. The vast majority of translocation-induced leukemias and lymphomas are restricted to cells of a single lineage arrested at a particular stage of development, indicating that the disrupted genes regulate vital processes limited to a subset of committed hematopoietic progenitors. Occasionally, as exemplified by leukemias arising from MLL gene abnormalities, more than one lineage or developmental stage is affected, suggesting the involvement of genes active in pluripotent or bipotent stem cells.

  4. The number of fusion genes with diagnostic and prognostic relevance is increasing rapidly. The hybrid mRNAs produced by these novel structures provide specific molecular probes for identifying affected patients who cannot be diagnosed readily by conventional means or who require chemotherapy tailored to the risk conferred by a particular genetic lesion.

  5. Studies in murine models, in which specific genes are mutated and homozygously inactivated in “knockout” mice or overexpressed in transgenic mice, have contributed new insights into the essential roles that are played in normal development and oncogenesis by genes discovered because of their proximity to the breakpoints of chromosomal translocations in the human leukemias and lymphomas.

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