A scientific team at the Dana-Farber Cancer Institute has clarified and explained a connection between Down syndrome and acute lymphoblastic leukemia (ALL), a link the medical community has long been aware of.
In a study (“Triplication of a 21q22 region contributes to B-cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation”) in Nature Genetics, the researchers track the genetic chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in ALL. Their findings are relevant not only to people with Down syndrome but also to many others who develop ALL, the team notes.
“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, M.D., Ph.D., of Dana-Farber's division of hematologic neoplasia. “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 ALL, specifically, the most common form of the disease known as B-cell ALL, or B-ALL, Dr. Lane and his colleagues acquired a strain of mice that 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,” Dr. Lane explained. “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.”
The researchers then scanned the mice's B cells to ascertain their “molecular signature,” the pattern of gene activity that distinguished them from normal B cells in mice. The chief difference was that in the abnormal cells, the group of proteins called PRC2 was not functioning. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.
“Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells,” wrote the investigators. “Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22, suppresses H3K27me3 and promotes both B-cell proliferation in vitro and B-ALL in vivo.”
“We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation,” noted Dr. Lane remarked. “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, which could potentially short-circuit the leukemia process in people with Down syndrome, the researchers suggest that drugs that switch on PRC2 could have an antileukemic effect in some of those people. Work is under way to improve these drugs, known as histone demethylase inhibitors, so they can be tested in cell samples and animal models.