| January 11,
Answer "One Small Question," and Advance The Quest to
Cure a Deadly Form of Cancer
Scientists Unlock a mystery related to Acute Undifferentiated
Scientists studying gene
regulation by a common protein compound have uncovered
its link to a fatal form of leukemia, in a breakthrough
that opens new lines of inquiry for researchers devoted
to finding a cure for the disease.
"This is how science works at its best. You begin with
an interest in how cells work, and it leads to an understanding
of the relationship of basic cellular proteins to a
disease," said Debabrata Chakravarti, PhD., Assistant
Professor of Pharmacology at the University of Pennsylvania
School of Medicine and leader of the research team that
made the discovery.
The findings are published today in the journal Cell.
Chakravarti's research, which began with his interest
in a specific aspect of cell transcription - the change
in a cell brought about by the action of DNA and protein
-- has uncovered what he describes as "a plausible mechanism"
for the function of a cancer-causing gene found in aberrant
bone marrow cells.
Bone marrow contains pluripotent stem cells, which
can give rise to lymphocytes and myeloid cells. Myeloid
cells contribute to the work of the body's immune system
-- but when they fail to differentiate, and therefore
cannot perform their natural function, they trigger
acute undifferentiated leukemia.
At the time of Chakravati's discovery, he and his group
were working to identify the function of a group of
cellular proteins, known collectively as INHAT, that
regulates gene activity. The protein complex functions
by modifying DNA through histones - the chain of proteins
that coil around DNA.
As they moved forward in defining the aspects of INHAT
that have to do with cell transcription, Penn's researchers
discovered the identity of one of the proteins in the
INHAT sequence is SET -- a putative oncogene.
"SET is present in every cell, but it functions only
as an oncogene in patients suffering from acute undifferentiated
leukemia. Nobody knows why this is so -but we do know
that in leukemia patients it is always found fused to
a second protein called CAN," Chakravarti said. The
function of the SET-CAN fusion is also a mystery.
As they unraveled the INHAT protein sequence, the Penn
scientists were also able to identify the function of
SET. They now understand that in normal conditions,
SET "masks" histones by wrapping itself around the ends
of the protein chains, helping to prevent random commands
from using the histones on the DNA to activate genes
inappropriately - and therefore protecting the integrity
of every cell's function.
Now that SET's presence in healthy cells is understood,
it will be easier for scientists to decipher what the
protein's presence means when it appears as part of
SET-CAN in cancer cells, Chakravarti said.
"Previously, neither the function of SET nor CAN was
understood. Now that we understand at least one function,
we can investigate whether the SET-CAN fusion contributes
to leukemia by promoting aberrant histone modification,"
he said. "We can also investigate the separate function
of CAN. And we can investigate how these two proteins
alter one another."
"Our work answered one small question. But more important,
it opens up so many new avenues of research," he said.
The study was funded by grants from the National Institutes
of Health, the University of Pennsylvania Cancer Center
and the University of Pennsylvania Diabetes Center.
Members of Chakravarti's staff who assisted in the
research include Sang-beom Seo, PhD; Peter McNamara,
PhD; Soyoung Heo, and April Turner. The study was conducted
in collaboration with William S. Lane, PhD., of the
Department of Microchemistry and the Proteomics Analysis
Facility at Harvard University.