In science, technological advances often serve to deepen medical mysteries, as researchers peel away the next layer of the onion. For nearly a century, doctors have known that children with Down syndrome face a heightened risk of developing acute lymphoblastic leukemia (ALL) — and now they finally know why.

Geneticist Andrew Lane at the Dana-Farber Cancer Institute say they’ve discovered the genetic “chain of events” leading to the chromosomal abnormality that is Down syndrome, which in turn leads to the “cellular havoc” of ALL.

"For 80 years, it hasn't been clear why children with Down syndrome face a sharply elevated risk of ALL," Lane said in a university press release. "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."

Kids with Down syndrome incur a 20-times greater risk of developing ALL throughout childhood, in addition to heightened risk for heart defects, respiratory and hearing problems, and thyroid conditions. The cognitive impairment occurs when the reproductive process creates an extra copy of chromosome 21, either partial or whole. In the study, Lane and his colleagues experimented on a strain of laboratory mice developed to carry an extra copy of 31 genes found on chromosome 21 in humans.

“B-ALL occurs when the body produces too many immature B cells, which are a type of white blood cell that normally fights infections," Lane said, referring to the most common type of ALL. "When we tested the mice's B cells in the laboratory, we found they were abnormal and grew uncontrollably — just as B cells from B-ALL patients do."

Lane’s research team then scanned the B cells to ascertain the “molecular signature,” the pattern of gene activity differentiating from normal B cells in mice. Primarily, they found that groups of proteins called PRC2 had failed to function, a loss that somehow compelled the B cells to divide and reproduce though they had yet to fully mature. But to confirm whether this protein failure indeed causes the formation of B-ALL in kids with Down syndrome, the researchers focussed on the specific genes controlled by those two protein groups, this time using cells donated from patients. After measuring the activity of thousands of genes to compare those B cells with those from ALL patients with Down syndrome, the researchers found about 100 genes driving the cell growth and division.

But which of those genes were to blame? In the lineup, gene HMGN1 was implicated as responsible for the undue B cell division and proliferation characterizing ALL on a cellular level. "We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation," Lane said. "This provides the long-sought after molecular link between Down syndrome and the development of B cell ALL."

Yet no drugs presently exist that target the HMGN1 gene, suggesting that researchers might try drugs likely to repair the functioning of PRC2 — with hope for a leukemia treatment someday soon. ALL is the most common type of childhood cancer, according to the National Institutes of Health.

Source: Lane, Andrew, Chapuy, Bjoern, Lin, Charles Y., et al. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nature Genetics. 2014.