Researchers Uncover Link Between Down Syndrome and Childhood Leukemia
April 20, 2014
doctors have long known that people with Down syndrome have a heightened risk
of developing acute lymphoblastic leukemia (ALL) during childhood, they haven’t
been able to explain why. Now, a team of
Dana-Farber Cancer Institute
investigators has uncovered a connection between the two conditions.
a study posted online today by the journal 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.
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’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.”
with Down syndrome have an increased risk for a variety of health problems,
including heart defects, respiratory and hearing difficulties, and thyroid
conditions. Their risk for childhood ALL
is 20 times that of the general population.
syndrome occurs in people who have an extra copy of a single chromosome, known
as chromosome 21. The addition may
involve the entire chromosome or a portion of it.
trace the link between Down syndrome and ALL – specifically, the most common form
of the disease known as B cell ALL, or B-ALL – Lane, who is also a medical
oncologist in the Dana-Farber/Brigham
and Women’s Cancer Center Adult Stem Cell Transplantation Program, and his
colleagues acquired a strain of mice that carry an extra copy of 31 genes found
on chromosome 21 in humans.
occurs when the body produces too many immature B cells, which are a type of
white blood cell that normally fights infections,” 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.”
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.
confirm that a shutdown of PRC2 is
critical to the formation of B-ALL in people with Down syndrome, Lane’s team
focused on the genes controlled by PRC2. Using two sets of B-ALL cell samples – one
from patients with Down syndrome, the other from patients without the syndrome
– they measured the activity of thousands of different genes, looking for
differences between the two 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 silenced – as it is in the B cells of Down syndrome patients – those 100
genes respond with a burst of activity, driving cell growth and division.
question then was, what gene or group of genes was stifling PRC2 in Down syndrome patients’ B
cells? Using cells from the mice with an
extra copy of 31 genes, the investigators systematically switched off each of
those genes to see its effect on the cells.
When they turned off the gene HMGN1,
the cells stopped growing and died.
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.”
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 anti-leukemic 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.
other forms of B-ALL also have the same 100-gene signature as the one
discovered for B-ALL associated with Down syndrome, drug agents that target PRC2 might be effective in those cancers
as well, Lane added.
study reveals the power of applying new tools (mouse models, genomic and
epigenetic technologies, and an ever-increasing armamentarium of chemical
probes) to solve old mysteries, such as the molecular link between Down
Syndrome and leukemia,” said co-author Kimberly
Stegmaier, MD, a pediatric hematologist/oncologist in the Hematologic
Malignancy Center at Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center. “This is a fine example
of how the study of the molecular underpinnings of diseases associated with
cancer can reveal new insights about potential targeted treatments for these
malignancies and possibly even the underlying disease."
for the research was provided by the Conquer Cancer Foundation; the Lauri
Strauss Leukemia Foundation; the Leukemia & Lymphoma Society; the Alex
Lemonade Stand Foundation; the U.S. Department of Defense; the Israel Science
Foundation; the U.S. Israel Binational Foundation; the Stellato Fund; and the
National Institutes of Health awards CA15198-01 and CA172387-A01.
senior author of the study is David Weinstock, MD, of Dana-Farber and the Broad
Institute of Harvard and MIT. Co-authors
are Bjoern Chapuy, MD, PhD, Charles Lin, PhD, Trevor Tivey, Hubo Li, Elizabeth
Townsend, PhD, Diederik van Bodegom, PhD, Tovah Day, PhD, Shuo-Chieh Wu, Huiyun
Liu, Akinori Yoda, PhD, Gabriela Alexe, PhD, Anna Schinzel, PhD, Timothy
Sullivan, Kristen Stevenson, Donna Neuberg, ScD, Lewis Silverman, MD, Stephen
Sallan, MD, and James Bradner, MD, of Dana-Farber; Kimberly Stegmaier, MD, and
William Hahn, MD, PhD, of Dana-Farber and the Broad Institute; David Pellman,
MD, of Dana-Farber and the Howard Hughes Medical Institute; Jordan Taylor, and
Jacob Jaffe, PhD, of the Broad Institute; Sébastien Malinge, PhD, of Institut
Gustave Roussy, Villejuif, France; Michael Bustin, PhD, of the National
Institutes of Health; Geertruy te Kronnie, PhD, of the University of Padova,
Padova, Italy; Shai Izraeli, MD, of Sheba Medical Center, Tel Aviv, Israel;
Marian Harris, MD, of Boston Children’s Hospital; and John Crispino, PhD, of