Credit: Aaron Logan
Investigators believe they’ve uncovered information that explains the connection between Down syndrome and B-cell acute lymphoblastic leukemia (B-ALL).
In a letter to Nature Genetics, the team described how they tracked the chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in B-cell ALL.
Experiments in mice and patient samples revealed that the gene HMGN1 turns off the function of PRC2, which prompts B-cell proliferation.
“For 80 years, it hasn’t been clear why children with Down syndrome face a sharply elevated risk of ALL,” said the study’s lead author, Andrew Lane, MD, PhD, of Dana-Farber Cancer Institute in Boston.
“Advances in technology—which make it possible to study blood cells and leukemias that model Down syndrome in the laboratory—have enabled us to make that link.”
To trace the link between Down syndrome and B-ALL, the investigators acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21. B cells from these mice were abnormal and grew uncontrollably, just as they do in B-ALL patients.
The team set out to characterize the pattern of gene activity that distinguishes these abnormal B cells from normal B cells. They found the chief difference was that, in the abnormal cells, PRC2 proteins did not function. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.
To confirm that a shutdown of PRC2 is critical to the formation of B-ALL in Down syndrome patients, the investigators focused on the genes controlled by PRC2. Using 2 sets of B-ALL cell samples—1 from patients with Down syndrome and 1 from patients without it—they measured the activity of thousands of different genes, looking for differences between the 2 sets.
About 100 genes were much more active in the Down syndrome group, and all of them were under the control of PRC2. When PRC2 is silenced, those 100 genes respond with a burst of activity, driving cell growth and division.
The investigators then wondered what gene or group of genes was stifling PRC2 in Down syndrome patients’ B cells. Using cells from the mouse models, the team systematically switched off each of the 31 genes to determine its effect on the cells. When they turned off HMGN1, the cells stopped growing and died.
“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” Dr Lane said. “This provides the long-sought-after molecular link between Down syndrome and the development of B-cell ALL.”
Although there are currently no drugs that target HMGN1, the investigators suggest HDAC inhibitors that switch on PRC2 could have an antileukemic effect in patients with Down syndrome. Work is under way to improve these drugs so they can be tested in preclinical experiments.
As other forms of B-ALL also have the same 100-gene signature as the one discovered for B-ALL associated with Down syndrome, agents that target PRC2 might be effective in those cancers as well, Dr Lane noted.
