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Chromothripsis Event Touches off Development of Rare Form of Acute Lymphoblastic Leukemia

NEW YORK (GenomeWeb News) – Two forms of a rare subgroup of acute lymphoblastic leukemia form through chromothripsis, or catastrophic chromosome shattering, researchers from the Wellcome Trust Sanger Institute and elsewhere reported in Nature yesterday.

Acute lymphoblastic leukemia is a common childhood cancer, but a small percentage of those cancers are marked by the amplification of chromosome 21, which has both prognostic and therapeutic ramifications. Using a combination of genomic, cytogenic, and transcriptional analyses, researchers led by Newcastle University's Christine Harrison and the Wellcome Trust's Peter Campbell reconstructed how iAMP21 ALL develops.

"We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome," Harrison said in a statement

In sporadic cases of iAMP21 ALL, breakage-fusion-bridge repair cycles initiate the amplification of chromosome 21, followed by chromothripsis.

But the researchers noted that iAMP21 ALL is much more common among people born with a chromosomal abnormality called a Robertsonian translocation in which chromosome 15 and chromosome 21 are fused together. A person with this translocation has a 2,700-fold higher risk of developing iAMP21 ALL, the researchers estimated.

"Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL," Harrison said.

In people with Robertsonian translocations, iAMP21 ALL develops slightly differently: chromothripsis of the fused chromosome occurs first, followed by amplification.

For both processes, the researchers said, the end product is a chromosome with a gene dosage optimized for the development of leukemia.

"This is a remarkable cancer — for patients with iAMP 21 ALL we see the same part of the genome struck by massive chromosomal rearrangement," co-first author Yilong Li from the Wellcome Trust Sanger Institute said.

To trace this path toward iAMP21 ALL, the researchers examined 21 patients with sporadic cases of the cancer and 12 patients with Robertsonian translocations who developed the disease. Using cytogenetic tools, fluorescence in situ hybridization, and copy-number profiling, the researchers explored rearrangements and copy-number patterns in these cancers. They also sequenced five sporadic and four Robertsonian translocation-associated cases.

In people with sporadic iAMP21 ALL, Harrison and her colleagues found that two main events — break-fusion-bridge repair and chromothripsis — appeared to lead to the development of leukemia.

In one patient, for instance, the boundaries of the amplified region were marked by fold-back inversion rearrangements. These rearrangements, the researchers said, are indicative of break-fusion-bridge repair in which a telomeric double-strand break occurs during S phase and then is fused during G2 phase, creating a dicentric chromosome whose two centromeres are then pulled to opposite poles during the anaphase stage of mitosis, creating a bridge. That bridge then breaks during cytokinesis.

Also in that region, the researchers uncovered evidence of a cluster of back-and-forth rearrangements that varied in their orientations and copy numbers, pointing to a chromothripsis event having taken place.

Because of how the rearrangements linked genomic segments with different copy numbers together, the researchers could reconstruct the evolution of iAMP21 ALL.

They deduced "that chromothripsis occurred after two BFB cycles and was likely the final major event, stabilizing the chromosome."

In Robertsonian translocation-associated iAMP21 ALL, however, Harrison and her colleagues noted that the main events occurred in a slightly different order.

There, they found, chromothripsis involving sister chromatids of the Robertsonian chromosome occurred first. That shattered chromosome was then pieced back together into a derivative chromosome in which the copy number of various regions increased.

In some Robertsonian translocation-associated iAMP21 ALL cases, the researchers noted, one BFB cycle preceded the chromothripsis event.

In all of these cases, the chromosome also underwent partial or whole chromosome duplication.

As iAMP21 ALL is more common in people with in Robertsonian translocations, the researchers hypothesized that there is something about how the two chromosomes are fused together that predisposes them to chromothripsis.

Using FISH, they noted that the Robertsonian chromosome is dicentric. They said that during mitosis, mitotic spindles coming from opposite poles could attach to those sister kinetochores. Then during anaphase, the researchers said, those two sisters chromatids would lag, making them prone to chromothripsis.

Additionally, also using FISH in conjunction with sequencing, they found that the chromosome 15 centromere is lost in people with the Robertsonian translocation who develop iAMP21, a loss that possibly stabilizes the derivative chromosome.

Chromothripsis of chromosome 21, the researchers added, seems to spare amplified regions of the chromosome. This pattern, the researchers said, also reflects the consensus landscape profile of chromosome 21 in other cancers, averaged over thousands of samples from a variety of cancer types.

This, the researchers said, indicates that chromothripsis has a role in optimizing the copy-number landscape to maximize the selective advantage for the subsequent rounds of chromosome duplication.

The combination of BFB and chromothripsis, Harrison and her colleagues said, can shape the chromosome landscape better than any one process alone.

"What is striking about our findings is that this type of leukemia could develop incredibly quickly — potentially in just a few rounds of cell division," added Wellcome's Campbell.