Blocking a Single Protein Proves Toxic
to Myeloma Cells in Laboratory Studies
Researchers have found that cells from a blood-borne cancer called
multiple myeloma rely on the activity of a single protein, called
IRF4, for the activation of a wide range of genes responsible for
cell survival and spread. Blocking the production of this protein
can be strikingly effective in eliminating cancer cells in laboratory
models of multiple myeloma. Scientists at the National Cancer Institute
(NCI), part of the National Institutes of Health (NIH), published
their results in the June 22, 2008, issue of Nature, which
highlight this potentially powerful new therapeutic target in multiple
"These findings reveal a hitherto unknown and, for myeloma
cells, critical network of gene activity centered on this one protein," said
Louis M. Staudt, M.D., Ph.D., deputy chief of the Metabolism Branch
at NCIís Center for Cancer Research. "What we have now is
a new window of opportunity for therapeutic development in multiple
Multiple myeloma arises from blood plasma cells, antibody-producing
cells that develop from the immune systemís B cells. There is no
cure for multiple myeloma, though the disease can sometimes be
controlled with chemotherapy, stem cell transplantation, or newer
To expand the therapeutic options for multiple myeloma patients,
Staudt, Arthur Schaffer III, Ph.D., NCI, and collaborators employed
a system for identifying potential drug targets that was recently
developed in their laboratory on the basis of a phenomenon called
RNA interference (RNAi). This system employs small snippets of
RNA, called short hairpin RNAs, to effectively turn genes off one
at a time, and allows researchers to measure the subsequent effects
on cellsí survival and proliferation.
The researchers applied this system to 10 laboratory models of
multiple myeloma, each representing distinct genetic subtypes of
the cancer. In all of these models, the scientists found that quenching
IRF4 production caused the myeloma cells to die.
IRF4 is a transcription factor — a protein that helps to
activate other genes. The Staudt team noted that the list of genes
that interact with IRF4 in multiple myeloma cells included genes
that are normally activated, not in plasma cells but in mature,
activated B cells. This finding suggests that myeloma cells are
somehow able to redirect IRF4 to activate a genetic program that
it would not normally affect in plasma cells.
One gene in particular that stood out from the rest of the list
was an oncogene called MYC, known to play a significant role in
multiple myeloma and other cancers. Further investigations revealed
that IRF4 and MYC form a feedback loop: IRF4 activates MYC, and
MYC, in turn, activates IRF4 and — by extension — itself
and the myeloma-fueling gene networks that rely on IRF4.
The discovery that multiple myeloma cells are dependent on IRF4
for survival puts a new twist on a hypothesis known as oncogene
addiction. This hypothesis suggests that certain cancers rely on
the activity of a single mutated gene pathway for proliferation
and survival. If this Achilles' heel can be identified and shut
down therapeutically, the hypothesis contends, the cancer can be
However, the case of multiple myeloma and IRF4 differs slightly.
Although the gene for IRF4 is not mutated in multiple myeloma,
myeloma cells are addicted to the proteinís ability to activate
normally inactive genetic programs inappropriately. Therefore the
dependency of myeloma on IRF4 may be best described as non-oncogene
addiction, which is the dysfunction of a normal protein that is
required for cancer cell survival or spread.
For more information on Dr. Staudtís laboratory, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5780 or http://lymphochip.nih.gov/index2.html.
For more information about cancer, please visit the NCI website
at http://www.cancer.gov, or
call NCIís Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Shaffer AL, Emre TNC, Lamy L, Ngo VN, Wenming X, Wright G, Powell
J, Dave S, Yu X, Zhao H, Zeng Y, Chen B, Epstein J, and Staudt LM.
IRF4 addiction in multiple myeloma. Nature. Online June