Clustering of Translocation Breakpoints

By Segal, Mark R.; Wiemels, Joseph L. | Journal of the American Statistical Association, March 2002 | Go to article overview

Clustering of Translocation Breakpoints


Segal, Mark R., Wiemels, Joseph L., Journal of the American Statistical Association


1. INTRODUCTION

Translocation is defined as the physical movement of genetic material between two nonhomologous chromosomes. In the simplest case, formation of a translocation involves double-strand breaks on two chromosomes followed by the aberrant fusion of the DNA free ends to the wrong partner chromosome. The resulting two derivative chromosomes with swapped arms can be viewed on a glass slide preparation of chromosomes, or a karyotype, of a patient's cells. At the level of the DNA sequence, specific genes may be split in two, resulting in the fusion of two genes not normally associated with each other. This resultant juxtaposition of two cellular genes can generate chimeric protein products in which the functional domains of two separate genes are fused together and/or can alter regulation of gene expression (Rabbitts 1994). More than 600 different acquired translocations in the neo-plastic diseases have been described. A given translocation between two particular cellular genes is consistently associated with a specif ic tumor type. This permits the development of diagnostics and therapeutics based on particular gene fusion products.

Translocations in the leukemias, our focus here, usually result in the formation of a chimeric protein in which the proximal end of one protein is fused to the terminal end of another protein. These proteins are usually transcription factors-proteins in the nucleus that control the expression of other genes involved in the growth and development of blood cells. When the normal development of blood stem cells is disrupted by the aberrant fusion transcription factor, leukemia may result. Genes are structured with protein-coding regions, or exons, interspersed with noncoding regions, or introns. Translocations that produce chimeric oncoproteins are constrained to occur within specific introns to preserve the ordering of exons necessary to generate an oncoprotein. However, within susceptible introns there is great latitude as to where the DNA may be broken and refused on either chromosome. This breakage/refusion site is called a "breakpoint" and is unique to each individual patient diagnosed with a particular tr anslocation.

One of the most common translocations in leukemia is the fusion of the TEL gene on chromosome 12 to the AML1 gene on chromosome 21. This translocation occurs in 25% of cases of childhood acute lymphoblastic leukemia, the most common cancer of childhood. We have shown that the TEL-AML1 fusion occurs prenatally in most children who develop this form of leukemia, even up to age 14 (Wiemels et al. 1999a; Wiemels, Ford, Van Wering, Postma, and Greaves 1999b). Despite this knowledge of the temporal origin of the translocation, little is understood about the process of fusion formation. Considered a "master" transcription factor, AML1 is a critical regulator of the development of nearly all blood cells. Blood cells develop from embryonic precursor cells, or stem cells, into functional types, such as red blood cells, T cells, and B cells. The TEL-AMLl protein is thought to result in the aberrant repression of genes that are normally induced by AML1 during the process of differentiation, or development of blood stem cells into functional types (Guidez et al. 2000). With the process of differentiation "frozen," the blood stem cells may gain a form of immortality, one component of the leukemic cell phenotype. The fusion occurs within the 14,000 base pair (bp) intron 5 of TEL and large 160,000 bp intron 1-2 of AML1. Both TEL and AML1 are involved in a various other translocations in other lymphoid and myeloid leukemia subtypes in children and adults (Greaves 1999), making the study of translocations involving these genes applicable to a wide range of the disease.

The elucidation of some common translocation breakpoint sequences in the lymphomas has resulted in a clear causal mechanism. Very tight clustering has been observed, which implicates the involvement of "recombination site sequences" (RSSs) in the formation of such translocations (Jager et al. …

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