It’s been frequently asked why people with Down syndrome have a higher risk than most of developing leukemia. For about 80 years, it was a mystery. Recently, a connection between people with Down syndrome and having a heightened risk of developing acute lymphoblastic leukemia was discovered.
Down syndrome is a common genetic disorder. It occurs in one out of 800 live births. It causes birth defects, medical problems, and some degree of learning disabilities. In fact, Down syndrome is the most common genetic cause of mild to moderate learning disabilities.
This disorder is a complication with chromosome pair 21. There are a few causes of this problem. There could be extra genetic material on chromosome 21 which may be caused by an extra chromosome. This is called Trisomy 21. This is the result of an error in cell division in the egg or sperm.
It can also develop from extra chromosomes in some cells. This form is called Mosaic Trisomy 21.The last cause could be that part of the chromosome has broken off and reattached to another chromosome. This is called translocation trisomy. In about one third of people, the translocation is inherited from a parent.
Leukemia is a form of cancer that initiates in blood-forming tissue. The disease is characterized by the unrestrained growth of blood cells (usually leukocytes) in the bone marrow. White blood cells are a fundamental component of the body’s immune response. The leukemia cells crowd and substitute normal blood and marrow cells.
Children born with Down syndrome are at an increased risk of having thyroid conditions, heart defects, and respiratory and hearing problems. Even worse is that their risk for developing childhood acute lymphoblastic leukemia is twenty times higher than that of the average, healthy person.
“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,” said the study’s lead author, Andrew Lane, MD, PhD, of Dana-Farber’s Division of Hematologic Neoplasia.
Researchers discovered that the primary difference was that in the abnormal cells, the group of proteins, called PRC2, was not functioning. By some means, the loss of PRC2 was prompting B cells to divide and thrive before they were fully mature.
To confirm that a shutdown of PRC2 is critical to the development of acute lymphoblastic leukemia in those with Down syndrome, Dr. Lane’s team directed their attention to the genes that PRC2 was in control of. By using two sets of acute lymphoblastic leukemia cell samples (one from patients with Down syndrome, the other from patients without the syndrome), they measured the activity of thousands of different genes. While doing this, they looked for differences between the sets. About 100 genes turned out to be much more active in the Down syndrome group, and all of them were under control of PRC2. When PRC2 is repressed, those 100 genes respond with a spurt of activity which motivates the growth and division of cells.
The question then was, what gene or group of genes was stimulating PRC2 in Down syndrome patients’ B cells? Through the use of cells from mice with an extra copy of 31 genes, the investigators switched off those genes to see what effect it produced on the cells. When they turned off the gene HMGN1, the growth of the cells was halted and they died.
“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” Lane remarked. “This provides the long-sought after molecular link between Down syndrome and the development of B cell ALL.”