Download genomic stability in mds - Aplastic Anemia and MDS International

GENOMIC STABILITY IN MDS
Christine O’Keefe, Ph.D. Cleveland Clinic Taussig Cancer Center
Myelodysplastic syndromes are disorders that affect the body’s ability to properly make blood cells.
In about half of the people with this disease, the chromosomes in the blood cells and bone marrow stem cells
(the cells responsible for blood production) have been damaged. These defects are characteristic of
myelodysplastic syndrome, and they can have an impact on the treatment and the progression of the disease.
A standard technique, called metaphase chromosome analysis or karyotyping, is routinely used to detect
these changes. However, karyotyping is not very sensitive and can only identify very large changes. It is
possible that smaller chromosomal changes exist in the blood cells of patients with myelodysplastic
syndrome. These so-called cryptic changes may also have an impact on diagnosis and treatment, but our
standard clinical tests cannot detect them.
Recently, a new technique called single nucleotide polymorphism (SNP) arrays have been
developed that can detect much smaller physical changes on chromosomes. Gene microarrays are similar to
computer chips and allow us to quickly examine all the chromosomes of an individual and will greatly
increase the number of patients we can test. Our laboratory has a very large collection of DNA from patients
with myelodysplastic syndrome and other related diseases. Also, we have established a specialized clinical
program for these diseases, therefore we will have access to enough patients to perform our study properly.
We plan to find small chromosomal changes in patients with seemingly normal chromosomes and correlate
them with disease subtypes. The presence of such changes will be correlated with another marker of
chromosomal instability, telomere length, and with the expression of DNA repair genes. If cryptic
chromosomal changes do correlate with disease subtype or response to treatment, diagnostic tests can be
designed to detect these changes. Ultimately, our use of genomic SNP array technologies will be helpful in
the future use of this new tool to study other diseases.
Gamma-secretase inhibitors as therapeutic intervention in bone marrow failure syndromes
Lisa M. Minter, PhD, University of Massachusetts, Amherst
Recent research suggests that many patients with aplastic anemia are actually experiencing a form of
autoimmune disease whereby their body’s immune cells mistakenly perceive the self-renewing populating of
bone marrow cells as “invaders” and try to destroy them. This results in the loss of red blood cells, white
blood cells and platelets from the circulation, and puts patients at increased risk of anemia, infection and
bleeding. The autoimmune response that proceeds during aplastic anemia is similar in nature to the
autoimmune response that causes the symptoms of another disease, multiple sclerosis, but the targeted cells
are different in the two diseases. Our lab studies a protein, Notch, which we recently discovered was critical
to this autoimmune response. When we gave mice a drug called a “gamma-secretase inhibitor” and then tried
to induce in them a form of multiple sclerosis, we found that the symptoms in mice receiving the gammasecretase inhibitor were greatly reduced, compared to mice who received a placebo. Gamma- secretase
inhibitors work to prevent the actions of a number of proteins, but a major target of their inhibition is the
protein, Notch. Thus, by preventing the activity of Notch proteins by using our gamma-secretase inhibitor,
we could lessen the severity of an autoimmune disease. Combining this observation with recent indications
that aplastic anemia may be the result of an autoimmune response, we wanted to ask whether gammasecretase inhibitors have any potential therapeutic value in the treatment of aplastic anemia. We will conduct
experiments using a recently developed mouse model of bone marrow failure. We will give some mice the
gamma-secretase inhibitor and other control mice a placebo, then we will induce bone marrow failure in both
groups of mice to determine whether the gamma-secretase inhibitor protects the self-renewing bone marrow
population from destruction. If successful, gamma-secretase inhibitors may provide additional treatment
options for patients with aplastic anemia for whom no suitable bone marrow donor may be available.
A NOVEL APPROACH FOR THE STUDY OF GENETIC PREDISPOSITION IN APLASTIC
ANEMIA AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA USING HIGH-DENSITY
ARRAYS.
Luikasz P. Gondek, M.D., Cleveland Clinic Taussig Cancer Center
The basis for human diversity can be found in over a million subtle differences in hundreds of
thousands of genes. These differences are not defects but often variants of normal genes. Their composition
may not only determine individual differences but also be responsible for varying susceptibility to many
diseases.
For many years we have investigated reasons why some unfortunate patients are affected by a disease
called aplastic anemia. This rare and often-fatal condition leads to disappearance of stem cells in the bone
marrow and results in interrupted production of all blood cells. Consequently, patients have severe anemia,
can bleed and suffer from life-threatening infections. aplastic anemia seemingly randomly strikes previously
healthy individuals and various theories were formulated to explain its occurrence, including genetic factors
viruses, chemical and drug exposures.
For the last century aplastic anemia incited intense clinical research which led to the discovery of
important functions of blood and marrow, and introduction of new therapies such as bone marrow
transplantation which is now used to cure many other diseases. So far we have not been able to pin down the
cause of aplastic anemia but we know that stem cell damage in this condition is mediated by immune cells
which turned against patient’s own bone marrow. Scientific evidence suggests that risk of aplastic anemia,
although induced by some external factors, may have complex genetic causes. However, until recently it was
hard to study hundreds of thousands of genes and their complicated interplay one by one with only very few
clues as to where to start the search. Recently, new research tools called single nucleotide polymorphism
(SNP) microarrays have been developed with which we can study differences in over one hundred thousand
of genes at once in an automated and very precise fashion. Gene microarrays are tiny chips similar to
microprocessors in computers and make possible to achieve progress in years, as opposed to decades
previously. In addition to the recognition of inherited genetic differences, microarrays allow for scanning of
the human genome for acquired defects. In the proposed study we want to take advantage of two aspects of
our research program that greatly increase the chances of success of our project factors: these powerful
genetic tools and our large collection of DNA from patients that is needed for proper analysis. Over years we
have established a very specialized clinical program in aplastic anemia and other similar disease, thus, we
see many patients that are required for this complex study. We plan to find gene variants and their
combinations that coincide with the aplastic anemia and are otherwise only rarely present in healthy
population. Individual gene variants will be correlated with subtypes of this disease. Such gene variants
could explain individual predisposition to aplastic anemia and the mechanisms as to how it develops. In
addition, a very precise genomic scan using SNP arrays of bone marrow cells may help to find acquired
disease-specific defects in chromosomes. This is a particularly important task, as leukemia often develops
from aplastic anemia and is characterized by such genomic defects. So far, our current crude methods have
not been helpful in finding such acquired genomic defects in aplastic anemia but it is likely that they may
exist in some patients who later develop leukemia. Should specific gene variants be identified in our study,
they would allow us to better understand disease mechanisms and generate diagnostic tests that could predict
individual risk and to identify those who could best benefit from specific types of therapy. Above and
beyond these specific goals, our application of genomic SNP array chips will be helpful in future application
of this powerful technology to study other serious disease including cancer.
P13 - Kinase Dysregulation in MDS
Seth Corey, M.D., UT-MD Anderson Cancer Center
The shortage of red blood cells, neutrophils and/or platelets found in aplastic anemia and MDS is due to their
premature death. There are critical biochemical signals inside a blood cell that keep that cell alive. When
those biochemical signals are no longer generated, the cell is more prone to die -- a process known as
apoptosis.
MDS is a disease of cell death. In the early stages of the disease, there is too much cell death. In the later
stages of the disease, there is too little cell death along with a failure of cells to mature.
We analyzed cells from patients with late stages of MDS and discovered that there is an enzyme which is
overly activated. We are studying how this over-active enzyme (known as AKT) not only prevents cell
death but also their maturation to normal appearing blood cells.
These studies provide insights into how MDS develops and rationale for use of drugs to block this enzyme.
Telomere Maintenance in Patients with Aplastic Anemia
Hinh Ly, Ph.D., Emory University, Pathology and Laboratory Medical Department
We are studying the biology of a unique DNA sequence, called telomere, which is located at the end of each
of our chromosomes. These "telomeres" act as a ruler to measure the life span of every cell in our body: the
shorter the telomeres are, the shorter the life span of the cell that contains them. We have discovered that
cells obtained from patients with AA or MDS have very short telomeres, and hence, die much quicker than
those of healthy individuals. The exact mechanism of how this occurs is still unclear. Therefore, we plan to
study blood cells collected from patients with the goal of understanding how the short telomeres can lead to
marrow failure syndromes. This study will provide us with a better understanding of the possible genetic
factors contributing to AA & MDS, which may lead to the development of novel and effective therapies
against these diseases.