Lead Story

Joining Forces:

Complementary approaches are piecing together the mysteries of chromosomal translocations and cancer

It has been almost 50 years since a “minute chromosome” was first identified in patients with chronic myelogenous leukemia (CML). This genetic abnormality, named the Philadelphia chromosome for where it was discovered, was the first genetic defect linked to cancer (Figure 1). Investigators initially believed that the Philadelphia chromosome resulted from the loss of genetic material. However, advances in cytogenetics over the next decade made it possible to view the true nature of this abnormality — the genetic material “missing” from chromosome 22 was not lost but “translocated” to chromosome 9.

It is now known that this specific translocation, found in 95 percent of patients with CML, fuses a proto-oncogene (a normal gene with oncogenic potential) on chromosome 9 (c-ABL) to a site on chromosome 22 known as a breakpoint cluster region. This hybrid oncogene, BCR-ABL, produces a constantly activated mutant protein (BCR-ABL), which wreaks the genomic havoc in the cell that ultimately causes CML but which also is the target of imatinib mesylate (Gleevec®), the first FDA-approved treatment to target a translocation-specific fusion protein.

Since the 1970s, chromosomal translocations have been associated with several types of blood cancers, and they are recognized increasingly as key players in solid tumors as well. Today, cytogenetic testing is performed frequently in the clinic to determine which chromosomal translocations are present in patient samples, helping facilitate diagnosis as well as treatment planning. But although we have come a long way in 50 years, we have yet to fully understand the molecular mechanisms behind these deadly chromosomal rearrangements and why they happen so often in the same chromosomal locations. Instead of treating the resulting cancer, can we prevent them from occurring in the first place? Researchers in the Center of Excellence in Chromosome Biology at CCR are putting together answers to these questions.

Since the 1970s, chromosomal translocations have been associated with several types of blood cancers, and they are recognized increasingly as key players in solid tumors as well.

Today, cytogenetic testing is performed frequently in the clinic to determine which chromosomal translocations are present in patient samples, helping facilitate diagnosis as well as treatment planning. But although we have come a long way in 50 years, we have yet to fully understand the molecular mechanisms behind these deadly chromosomal rearrangements and why they happen so often in the same chromosomal locations. Instead of treating the resulting cancer, can we prevent them from occurring in the first place? Researchers in the Center of Excellence in Chromosome Biology at CCR are putting together answers to these questions.

Taking a Global View

Tom Misteli, Ph.D., Head of the Cell Biology of Genomes Group in CCR’s Laboratory of Receptor Biology and Gene Expression, arrived at NCI nine years ago with the task of building an imaging program. Within a few years, he gradually began to apply in vivo imaging techniques to chromosome biology and specifically to understanding how genome organization affects genome regulation (see “The Right Place at the Right Time”). He and his CCR colleagues are now using high resolution microscopy, live-cell imaging, and computer simulation to study the positioning of entire chromosomes and particular gene loci within the nucleus in order to understand how these arrangements change during normal and aberrant physiological processes (Figure 2).

Figure 1. The Philadelphia chromosome—the result of a translocation between chromosomes 9 and 22 (circles)—is often found in the cells of patients with chronic myelogenous leukemia.

Far from being randomly scattered around the nucleus, chromosomes, sub-chromosomal domains, and individual genes are nonrandomly organized into discrete territories, or neighborhoods, within the nucleus. Although these entities may have preferred localizations, the patterns can change in response to the cellular environment. The distinct territory occupied varies with cell type, upon cell differentiation, and when cells exit the cell cycle, suggesting a link between positioning and genome function. The positioning is believed to influence gene expression programs as cells undergo changes throughout development and differentiation.

Positioning can determine direct interactions between genes, which in turn can regulate gene expression. In naïve T-helper immune cells, for example, when a specific region on mouse chromosome 11 (TH2) directly interacts with the lfng locus on chromosome 10, the locus is turned “off.” When these cells then receive a signal to differentiate, the two regions separate, and the lfng locus turns back “on.”