(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have identified a new
protein associated with acute myelogenous leukemia (AML). Several
lines of evidence point to a protein called Tribbles, named after
the furry creatures that took over the starship Enterprise in the
original "Star Trek" series. Tribbles was first described
in fruit flies.
“Tribbles had never been directly linked to human malignancy,”
says senior author Warren S. Pear, MD, PhD, Associate
Professor of Pathology and Laboratory Medicine. “This is a
new protein to human cancer and has a specific and overwhelming
effect when expressed in hematopoietic stem cells, the cell type
that gives rise to all elements of the blood.”
lines of evidence implicate Tribbles in AML. First, all mice engineered
to express Tribbles-2 (Trib-2) in hematopoietic stem cells developed
AML. They also found that Trib-2 inhibited C/EBPα, another protein
that is frequently mutated in AML patients. Additionally, expression
of the Tribbles protein was elevated in blood samples from AML patients,
further suggesting that it contributes to AML. Overall, the findings
suggest that Tribbles induces AML by inactivating the C/EBPα protein.
The results were published in this week’s issue of Cancer
AML is a malignancy that arises in white blood cells and develops
when there is a defect in immature immune cells in the bone marrow.
In AML, the uncontrolled, exaggerated growth and accumulation of
white blood cells leads to anemia and a deficiency of normal white
cells in the blood. AML is the most common type of leukemia in adults,
with an estimated 10,100 new cases reported each year.
Pear, also a researcher in the Abramson Family Cancer Research
Institute at Penn; first author and postdoctoral fellow
Karen Keeshan, PhD; and colleagues found Tribbles
by chance when looking for the molecular partners of another protein
called Notch. Notch is a molecular switch of sorts, activating gene
transcription in the nucleus of many types of cells, and depending
on the biochemical context, turns certain pathways on and others
Pear and colleagues knew from fruit fly studies that the Tribbles
protein was linked to cell growth and cell-fate determination and
is closely related to the Tribbles gene in mammals. In
fact, Tribbles is so named because, when mutated in flies,
it causes cells to proliferate uncontrollably.
Accumulating evidence from several groups shows that Tribbles functions
as a scaffold to bring together a complex that mediates protein
degradation. Protein degradation is required for normal cellular
function; however, data from the Pear lab suggests that mistakes
in the expression of the Tribbles gene may lead to degradation
of proteins that hold cancer in check, such as tumor suppressors.
“One of our current challenges is to determine what other
proteins Tribbles degrades to cause leukemia,” says Pear.
The findings in mice were also validated in a large database of
human cancer patients. In a survey of gene expression in AML patients,
high Tribbles expression was found in a subset of patients who had
been previously characterized by defects in C/EBPα.
According to Keeshan, “C/EBPα defects have also been identified
in lung cancer and other tumors, suggesting the possibility that
Trib2 dysregulation may be identified in other tumors. Furthermore,
linking Trib2 to human cancer adds further support to the notion
that targeting the protein degradation machinery will be a useful
strategy in treating malignancy.”
This work was funded by the National Institutes of Health, the
Leukemia and Lymphoma Society, and the Damon Runyon Cancer Research
Foundation. Co-authors, in addition to Pear and Keeshan, are Yiping
He, Olga Shestova, Lanwei Xu, Hong Sai, Carlos G. Rodriquez, Ivan
Maillard, John W. Tobias, and Martin Carroll, all from Penn, along
with Bas J. Wouters, Peter Valk, and Ruud Delwei from Erasmus Medical
Center (Rotterdam, Netherlands) and Jon C. Aster, Brigham and Women’s
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