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ABSTRACT

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

INTRODUCTION

The concept that cancer cells contain genetic information not found in normal cells has provided the impetus for molecular approaches to cancer research. A pivotal step in this progress was the realization that gross chromosomal changes—such as translocations, deletions, inversions and amplifications—can perturb genes intimately involved in carcinogenesis.1-3 Thus a major concern over the past two decades has been the identification of consistent chromosomal abnormalities in specific types of tumor cells, the isolation of genes affected by these changes, and the elucidation of their mechanisms of action and clinical correlations. A surprising dividend of this venture, aided by technology that permits one to create homozygous null animals by inactivating individual genes (e.g., “knockout” mice), has been the discovery of proteins that not only promote cancer but also have essential functions in normal cell development as well.4

Specific reciprocal translocations perhaps are the best example of how cytogenetic changes pave the way for cancer induction and spread. These nonheritable abnormalities occur in a high percentage of hematologic cancers—both leukemias and lymphomas—where they disrupt signaling pathways that enhance cell survival.4-7 Their actions can directly activate occult proto-oncogenes or, more ...

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