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Karen Kreeger
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Cells of Aggressive Leukemia Hijack
MLL
happens when a piece of chromosome 11 breaks off at the normal MLL-associated
gene. The broken gene attaches itself to another chromosome, resulting in a
fusion protein that eventually causes uncontrolled growth of blood cells.
The
lab of senior author Xianxin Hua, MD, PhD, an associate professor of
Cancer Biology at the Abramson
Family Cancer Research Institute, University of Pennsylvania School of
Medicine,
found that this runaway growth triggered by the fusion protein is blocked when
the gene for the normal protein is deleted from leukemia cells. This indicates
that the normal protein is required for MLL to proliferate. The findings appear
in the current issue of Cancer Cell, and are featured on the cover.
The chromosomal
breakages and reattachments of MLL, called translocations, are common in many
aggressive leukemias. Children with mixed lineage leukemia have a poor
treatment outlook because they do not respond well to standard therapies for
other types of leukemia, and they often suffer from early relapse after
chemotherapy.
MLL
translocations come in a variety of types, causing the fusion of the normal
gene with one of over 60 other genes on other chromosomes known to work in
human leukemias. The fusion protein triggers leukemia, partly through modifying
chromatin, a DNA-protein complex.
The
researchers also discovered that normal the MLL protein cooperates with the
fusion proteins via chemical modifications to chromosomes that regulate what
genes should be turned on or off; by increasing survival of leukemia cells; and
maintaining leukemia stem cells.
"This
research not only uncovers the crucial role of a normal protein key to the
development of MLL, but also how the cancer cells stay alive in the first place,"
says Hua. The unraveling of the new, yet little-anticipated, molecular player
behind MLL points to the normal MLL
gene as a potential target for new therapies, partly through repressing
leukemia stem cells.
Building
on this discovery, Hua's team will further investigate whether mixed lineage
leukemia cells are particularly "addicted" to normal MLL protein, a
non-oncogene, in their growth and survival and whether normal MLL proteins
specifically cooperate with other factors to sustain leukemia stem cells, with
the hope of searching for an Achille's heel of this aggressive leukemia.
Gary Koretzky, MD, PhD, professor of Pathology and
Laboratory Medicine at Penn, and Patricia Ernst, Ph.D, assistant professor of
Genetics, at
The study was funded partly by a National Institutes of Health (NIH) grant, a Leukemia and Lymphoma Society SCOR grant, and an NIH T32 training grant.
This
release and a related image can be found at: http://www.uphs.upenn.edu/news/News_Releases/2010/02/mixed-lineage-leukemia/
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