Unique role for blood formation gene identified
Dartmouth Medical School research reveals new pathway for stem cell
turnover
Hanover, NH--All blood cell production in adults depends on the
steady work of a vital gene that if lost results in early bone marrow
failure, Dartmouth Medical School cancer geneticists have found.
Their research reveals an unexpected role for the gene in sustaining
the adult blood-forming system, and opens novel strategies for
targeting the gene, which is often involved in a type of childhood
leukemia.
"We have identified a new pathway that is essential for blood stem
cell turnover," said team leader Dr. Patricia Ernst, assistant
professor of genetics and member of the Norris Cotton Cancer Center.
The pathway could be exploited for treating a rare but aggressive
infant leukemia, she added. These findings were reported in the
September issue of Cell Stem Cell.
The investigators created a mouse model to track the function of a
gene called MLL, which stands for Mixed Lineage Leukemia. The gene
acts in bone marrow stem cells and controls key aspects of their
growth to generate all the mature blood cells. If disrupted, it
cannot work properly, and leukemia can ensue.
"MLL is the most commonly affected gene in childhood leukemia in
children under a year of age; this particular type of leukemia has
one of the worst success rates with the existing cancer therapies,"
said Ernst, who first helped clarify the role of MLL as a
postdoctoral fellow at Harvard.
Many childhood leukemias result from mutations called translocations,
where gene pieces on chromosomes accidentally relocate and misalign.
In infant leukemia, the chromosome containing the MLL gene breaks
within MLL and ends up fused to a different gene. MLL fusion genes
likely co-opt normal MLL functions in blood cells, leading to the
overproduction of white cells and leukemia.
Previous studies indicated that MLL is critical for embryonic blood
stem cell development, but its role for the adult system was unknown.
In their mouse model, the researchers found that bone marrow failure
occurred as early as 14 days after they induced the experimental loss
of MLL, demonstrating the crucial role of MLL as "necessary for both
the development and maintenance of the body's blood supply,"
according to the researchers.
"We have shown that the adult blood-forming system depends on the
continuous actions of MLL," Ernst said. Moreover, with the mouse
model the scientists established to define normal MLL functions, they
can begin exploring how to craft new anti-cancer treatments, she
pointed out. "We and other groups can start designing targeted
therapies that inhibit cancerous forms of MLL that occur in childhood
leukemia and do not affect normal MLL function, which, based on our
studies in mice, would be fatal for the patient."
###
Coauthors of the publication are DMS graduate students Craig D. Jude,
Diyong Xu and Erika Artinger, research assistant Leslie Climer and
Ernst's colleague Jill Fisher of the Dana Farber Cancer Institute,
Boston.
This work was supported by funding from the National Institutes of
Health, the Sydney Kimmel and V Foundations, and the American Cancer
Society.
Public release date: 12-Sep-2007
Contact: Hali Wickner
dms.communications@
Dartmouth Medical School
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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