Issue #10
July 2011
In This Issue
It's Your Foundation
DBAF & DBAC Fund Research
DBA Family Day
Show Us Your Logo!
DBA Fact
Where Are You?
DBAF Journal Club
The Diamond Blackfan Anemia Foundation (DBAF) is
committed to keeping you updated and connected to
the entire DBA community. The Diamond Blackfan
Anemia Foundation is YOUR Foundation! We
encourage you to share your ideas, photos, and
stories for our website and upcoming newsletters.
Contact us at DBAFoundation@juno.com.
DBAF & DBAC Working
Together
It's YOUR Foundation
We are pleased to announce the funding of Dr. Johan
Flygare's project titled: Identification of Genetic and
Chemical Modifiers of Erythropoiesis in Diamond
Blackfan Anemia.
This project
is significant
for many
reasons.
The
Diamond
Blackfan
Anemia
The Diamond Blackfan Anemia Foundation is committed Foundation
to supporting DBA patients, families, and research. It is (DBAF) is
only through the support of our friends and families that grateful to
we continue to fulfill our mission. We recognize that
Diamond
there are many organizations and charities worthy of
Blackfan
your support, and we are grateful to our supporters and
Johan Flygare
Anemia
donors that allow us to fund critical DBA research
Canada
projects.
(DBAC) for their generous support in helping to fund
Dr. Flygare's work. DBAC received charitable status
only three months ago and has graciously offered to
The Diamond Blackfan Anemia Foundation currently has
fund $10,000 of this $50,000 project. This first
numerous research proposals seeking funding. These
collaboration between DBAF and DBAC is certain to
worldwide research projects have the potential to answer
be just the beginning of many joint ventures. We are
questions, to identify genes, to unlock the mystery of
proud to partner with DBAC and look forward to
remission, and to provide insights into therapeutic
supporting each others' efforts. Way to go American
agents. These projects also represent the hopes of all of
and Canadian families and friends for joining forces to
us for a better understanding, better treatment options,
fund DBA research in Sweden!
and possibly a cure for our "orphan disorder."
It is exciting to witness the worldwide interest in DBA
research, and we are confident that our families and
friends will get involved to insure that funding these
projects becomes a reality. It is up to us to make this
happen! We cannot fund DBA research without YOUR
help. Let's get these projects funded!
Donating is easy and all contributions are taxdeductible. Please visit our Donate Page
for details. If you are interested in organizing a
fundraiser to benefit the DBAF, please contact us
at DBAFoundation@juno.com.
THANK YOU!
Upcoming Events
Zumba Fitness Fundraiser
for DBA
July 31, 2011
Berea Recreation Center
Berea, Ohio
Contact:
Carol Mancuso
c-mancuso@sbcglobal.net
Friends of DBAF Golf
Outing & Silent Auction
September 17, 2011
Cherokee Hills Golf Club
Valley City, Ohio
Contact:
Jim and Carol Mancuso
c-mancuso@sbcglobal.net
Jack's Fight for a Cure
DBA Dinner & Dance Gala
to benefit DBAC
November 11, 2011
Orangeville Agricultural Center
Orangeville, Ontario
Canada
Contact:
Dr. Flygare's project goal is to develop better
treatments for DBA by identifying chemical compounds
and molecular pathways that promote proliferation of
RPS19-deficient erythroid progenitor cells.
This project has two parts: In the first part, Dr. Flygare
will identify genes, that when down-regulated, allow
RPS19-deficient erythroid progenitors to proliferate at
normal levels. The findings of this study will increase
the understanding of DBA pathogenesis and generate
a list of genes and pathways that potentially can be
targeted to treat DBA.
In the second part, Dr. Flygare will use erythroid
progenitors from a new and exciting Dox-inducible
mouse model to screen for compounds that can
rescue the RPS19-related erythroid defect. The
chemical screens will lead to identification of
compounds that rescue proliferation of RPS19deficient erythroid progenitors. Such compounds will
be lead compounds for the development of new drugs
for DBA. By studying the mechanism by which these
compounds influence the proliferation of RPS19deficient erythroid progenitors, more will be learned
about DBA pathogenesis.
The DBAF and DBAC are pleased and proud to be
able to fund Dr. Flygare. This talented young
investigator is well known to the DBA community, and
has been supported by the DBAF throughout his
career. Dr. Flygare stated, "During my ten years of
scientific training I have focused on DBA-related
research. This has been an excellent preparation for
becoming an independent researcher with the longterm goal to develop novel treatments for DBA." Dr.
Flygare has completed postdoctoral fellowships in Dr.
Stefan Karlsson's lab in Lund University, Sweden and
in Dr. Harvey Lodish's lab at The Whitehead Institute
for Biomedical Research, Boston, MA. Dr. Flygare has
recently established his own lab in Sweden and has
earned the support and respect of many distinguished
DBA researchers. We are grateful to Dr. Flygare for
his continued interest in Diamond Blackfan Anemia
and we wish him and his colleagues continued
success.
DBA Family Day 2011 - Seattle,
WA
Janet Pereira
janet@jacksfightforacure.com
Ongoing Fundraisers
Wristbands Available
Contact:
Twila Edwards
twilak@cox.net
A fun-filled, informative day
was had by all!
Seattle Children's Hospital
graciously hosted a DBA
Family Day giving DBA
families the opportunity to
meet, share their stories,
and learn more about
Diamond Blackfan Anemia.
Dr. Akiko Shimamura and Kathleen McGregor
MN/MPH organized the event. Presentations were
given by Dr. Akiko Shimamura, Dr. Bertil Glader, Dr.
Laurie Burroughs, and Dr. Sioban Keel. Thanks to all
for making DBA
Family Day 2011 Seattle a smashing
success!
Tribute Cards Available
(2 styles)
In honor of...
In memory of...
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
716.674.2818
Shelly Marquer,
Kendra Kofron, Ruby
Swanson, Josh
Hollingsworth, Ed Fields and Kelsey Fields were some
of the adult patients able to attend and participate in
the day's activities.
(Love the shirt, Shelly!)
DBA Cookbooks Available
Contact:
Betty Lightner
betty.lightner@gmail.com
To download your order form:
http://issuu.com/bhivemom/docs/cookbook_order_formpdf
Take the Challenge ~ Show Us
Your Logo
T-shirts, hats, coffee
mugs, face paintings,
tattoos, bags, pumpkins
... our logo is showing up
everywhere! We are
thrilled that our beautiful
logo is proudly being
worn and displayed by
patients, families, and
friends.
It was up, up, and away
for Amelia Lamb, her
family, and our logo. On a recent trip to Disney World,
the Lenexa, KS family took a hot air balloon ride and
brought us along for the peaceful, relaxing ride.
Thanks Lamb family!
Good Search/Good Shop
Raise money for DBAF just by searching the web and
shopping online!
Just download the GoodSearch - Diamond Blackfan
Anemia Foundation - DBAF toolbar at
http://www.goodsearch.com/toolbar/diamond-blackfananemia-foundation-dbaf
Here's the challenge: we'd
like to see how many
places we can show off our
logo! Snap a picture sporting
our logo and send us your
story. Draw it, print it out,
wear it, wave it, tattoo it,
carve it... be creative! Take
us to school, on vacation, to
the hospital, on a plane, to the game, in your home...
anywhere! Show us your logo! Send your photos
and stories to DBAFoundation@juno.com.
DBA Fact #5
Our Facebook page posts DBA facts
written by DBA nurse, Ellen Muir, RN,
MSN, CPON. We are pleased to share
these fast facts with our patients and
families. Thanks, Ellen!
Quick Links
Make a Donation
Ellen Muir
DBA Fact #5 What you should
consider before SCT (stem cell
transplantation/ bone marrow
transplant):
Our Website
Join the DBA Yahoo Group
Decide what your reasons are for transplant. Is it
:: 716-674-2818
because you want it? Are you sick and tired of
transfusion and chelation or steroid therapies enough
that it is affecting your quality of life? Or is it because
you need it? Maybe you have developed antibodies,
making it impossible to find a compatible blood donor
and are resistant to steroids. Maybe you have
developed aplastic anemia or myelodysplastic
syndrome (MDS) - which are other bone marrow
failure syndromes affecting red cells, white cells and
platelets. Maybe steroids do not work and you also
have the hemochromatosis gene (which makes you
load iron even if not transfused).
You should talk with someone who has been through
the transplant process and absolutely speak to your
hematologist in detail. Please call the DBAR (877DBA-NURSe), as we have the most experience and
information about the outcomes of these types of
transplants. Dr. Vlachos has spoken to transplant
doctors in other states and has even stopped
transplant from taking place, if she felt it was too much
of a risk. Complete information regarding transplant
can be found at www.marrow.org.
Risks vs. benefits. The benefits must outweigh the
risks.
Risks:
Death may occur due to complications including: GVH,
rejection, infection.
Graft vs. Host Disease (GVHD) - the donor cells can
actually attack different parts of the recipient's body,
the body's natural defense tries to fight the donor
marrow, as it is seen as "foreign." Skin - GVH can
cause a rash, discoloration, peeling and sloughing.
Gastrointestinal - can cause the GI tract (from the
mouth to the anus) to slough off causing sores and
diarrhea.
Rejection - your own immune system is strong enough
to reject the donor cells, this happens sometimes with
"mini transplant."
Infection - may be severe, even life threatening, if you
get something as simple as a cold or virus. Even your
food needs to be well cooked, no fresh fruits or
vegetables, no fast food, until the immune system
comes completely back to normal.
Cancer - DBA has a risk of cancer to begin with, even
if it is a small risk. The transplant requires
chemotherapy, which in itself can actually cause
possible cancer in the future.
Infertility - Chemotherapy can cause the inability of the
reproductive organs to work correctly.
Return of DBA -This can happen with a related donor
who has "silent" DBA. That is, they have the same
gene as the patient, but never knew because they
never had anemia or congenital anomalies which
sometimes go along with DBA. This is why the donor
needs to be carefully screened.
Benefits:
A successful transplant eliminates the need for
transfusion and steroids for treatment of anemia in the
future. It does not eliminate the 50% possibility of
passing it on to your children or the other risks
associated with DBA. DBA is in all your genes.
Transplant "fixes" the bone marrow production of red
blood cells, but does NOT "cure" all aspects of DBA.
Where Are You?
Did you move? Need to add a new address? Are you a
recently diagnosed family? If you did not receive the16
page printed Spring/Summer DBA Newsletter in the
mail last month, it may mean we do not have your
current mailing address. To stay informed, update your
contact information at
http://www.dbafoundation.org/registration.php
If you have any questions, contact us at
DBAFoundation@juno.com.
Journal Club
Why, oh why, is it so hard
to create a rock solid mouse
model for Diamond Blackfan
anemia? And why, oh why,
is such a model so
important? Well, the
importance lies in answering
fundamental questions in
DBA pathophysiology, such
as why a defect in
something as ubiquitous
Steven R. Ellis, PhD
and important as the
Research Directo
ribosome selectively affects
red cell production in DBA
patients. Further, having a
rock solid model of DBA would allow us to understand
the mechanisms that underlie remission or the
response to drugs like steroids which in turn could
help develop new therapeutics that might work by
related mechanisms.
So let's begin this month's Journal Club by discussing
other models of Diamond Blackfan anemia. First we
have the yeast model, and while this model showed
us how to study ribosome synthesis and set the stage
for showing a ribosome synthesis defect in DBA
patients, yeast make beer and not blood, so this
model could only take us so far1. Next, we have the
zebrafish DBA model and various human cellular
models of DBA, and while these models have given us
tremendous insight into the relationship between
defects in ribosome synthesis and the activation of
cell death signaling pathways through p53, these
models lack complex aspects of mammalian
physiology that may contribute to clinical features of
DBA2,3.
So what's the hold up in creating a mouse model of
DBA? And why mice, whatever happened to the
laboratory rat? Well, mice rather than rats, because
mice have been the darlings of the mammalian
genetics world for some time now and workers in the
field have created a number of tools that allow the
ready manipulation of the mouse genome. One such
tool is the ability to selectivity inactivate specific
genes, essentially at will. So why not just inactivate,
let's say one of the two copies of RPS19 in the mouse
genome, which in principle would recapitulate the
genetic lesion found in approximately 25% of DBA
patients? Well, this has been done and quite a while
ago I might add, and although it may have recreated
the genetics underlying DBA, it had no measureable
effect of any physiological parameters of the
knockout mouse, including red blood cell
production4. Since this time other mouse models of
DBA have been described, but the anemia observed is
extremely mild, or the mice do not fully recapitulate
salient clinical features observed in DBA patients5,6.
Which brings me to this month's Journal Club article,
which none other than Dr. Jeffrey Lipton has dubbed
"a very important paper." The article, "RibosomeMediated Specificity of Hox mRNA Translation
and Vertebrate Tissue Patterning" by Maria Barna
and colleagues published in Cell (2011) 145, 383-397
does not unfortunately give us a DBA mouse, but it
does show how a change in expression of a ribosomal
protein may have tissue specific effects and may also
provide experimental insight into why making a DBA
mouse has been so challenging. The authors of this
manuscript show that the gene encoding Rpl38, a
large subunit ribosomal protein, when mutated gives
rise to skeletal abnormalities. It is important to note
that RPL38 in humans has not been identified as a
DBA gene. In fact, RPL38 may be distinct from the
DBA genes identified to date in that it is not required
for ribosome synthesis per se, but instead seems to
play a specialized regulatory role in ribosome function
which is to regulate the translation of certain HOX
genes involved in skeletal development. So, rather
than being an integral component of all ribosomes
required for their production, Rpl38 appears to be
highly expressed in certain tissues where it influences
ribosome function. And as such, its loss preferentially
affects those tissues where it is highly expressed.
So could there be an analogous situation in DBA? Are
the ribosomal proteins affected in DBA playing highly
specialized roles in ribosome function in developing
red blood cells? This is a tough call. The DBA genes
identified to date all encode ribosomal proteins
needed to make ribosomes, not just regulate their
function. There is no evidence to date to suggest
that these proteins are more important for making
ribosomes in one tissue relative to another. So what
is it about RPS19 and the other DBA genes that
selectively give rise to anemia and the other
heterogeneous congenital anomalies observed in this
disease? The answer may lie in another observation
made in the Barna article, which is that when one
looks at the expression level of ribosomal protein
mRNAs from one cell and tissue type to another there
is considerable heterogeneity, such that a protein
expressed at a high level in one tissue type may be
expressed at a much lower level relative to other
ribosomal proteins in another tissue. This
observation seems to support the view that many
ribosomal proteins are normally expressed in excess
of what may be needed to produce ribosomes in a
particular tissue, with excess protein degraded.
While this situation may seem wasteful, the loss on
one of two copies of a gene coding for a protein
produced in excess of that needed normally may not
trigger a disease state. In the case of DBA, on the
other hand, genes like RPS19 may not produce much
by way of excess protein in certain tissues, for
example red cell precursors, and so when one gene is
lost by mutation it triggers an adverse effect in these
tissues. We advanced such a hypothesis several
years ago now7.
With our present lack of detailed understanding of the
levels of ribosomal protein expression in different
tissues between mice and man it is impossible to test
this hypothesis and further, to predict which mouse
ribosomal proteins may give a specific effect on red
cell development similar to that observed in DBA
patients. While it may be difficult to specifically
predict which ribosomal proteins in mice may be DBA
proteins, there is room for optimism since as Barna
and colleagues have shown, ribosomal proteins
continue to surprise us. I wouldn't be too terribly
surprised to finally see a rock solid mouse model for
DBA coming from a ribosomal protein gene that may
not even be affected in human patients. Such a
mouse would nevertheless provide an amazingly
resource for DBA research.
1. Leger-Silvestre I, Caffrey JM, Dawaliby R, et al. Specific
Role for Yeast Homologs of the Diamond Blackfan Anemiaassociated Rps19 Protein in Ribosome Synthesis. J Biol
Chem. 2005;280:38177-38185.
2. Danilova N, Sakamoto KM, Lin S. Ribosomal protein S19
deficiency in zebrafish leads to developmental abnormalities
and defective erythropoiesis through activation of p53 protein
family. Blood. 2008;112:5228-5237.
3. Dutt S, Narla A, Lin K, et al. Haploinsufficiency for
ribosomal protein genes causes selective activation of p53 in
human erythroid progenitor cells. Blood;117:2567-2576.
4. Matsson H, Davey EJ, Draptchinskaia N, et al. Targeted
disruption of the ribosomal protein S19 gene is lethal prior to
implantation. Mol Cell Biol. 2004;24:4032-4037.
5. Devlin EE, Dacosta L, Mohandas N, Elliott G, Bodine DM.
A transgenic mouse model demonstrates a dominant
negative effect of a point mutation in the RPS19 gene
associated with Diamond-Blackfan anemia. Blood;116:28262835.
6. McGowan KA, Li JZ, Park CY, et al. Ribosomal mutations
cause p53-mediated dark skin and pleiotropic effects. Nat
Genet. 2008;40:963-970.
7. Ellis SR, Massey AT. Diamond Blackfan anemia: A
paradigm for a ribosome-based disease. Med Hypotheses.
2006;66:643-648.