Credit: Beth A. Sullivan
Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.
Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.
In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.
They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.
And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.
“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.
“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”
To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.
For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.
In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.
The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.
“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,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”
