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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

It's YOUR Foundation

DBAF Logo
 

The  Diamond Blackfan Anemia Foundation is committed to supporting DBA patients, families, and research.  It is only through the support of our friends and families that we continue to fulfill our mission. We recognize that there are many organizations and charities worthy of your support, and we are grateful to our supporters and donors that allow us to fund critical DBA research projects.

 

The Diamond Blackfan Anemia Foundation currently has numerous research proposals seeking funding.  These worldwide research projects have the potential to answer questions, to identify genes, to unlock the mystery of remission, and to provide insights into therapeutic agents. These projects also represent the hopes of all of us for a better understanding, better treatment options, 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 tax-deductible. 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:  
Janet Pereira
janet@jacksfightforacure.com




Ongoing Fundraisers 

 

Wristbands Available

Contact:
Twila Edwards

twilak@cox.net 




Tribute Cards Available

(2 styles)

In honor of...

In memory of...

Contact:

Dawn Baumgardner

dbaumgardner@dbafoundation.org

716.674.2818



donation donation



DBA Cookbooks Available

Contact:
Betty Lightner
betty.lightner@gmail.com
To download your order form:

http://issuu.com/bhivemom/docs/cookbook_order_form-pdf


cookbook cover 




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-blackfan-anemia-foundation-dbaf

   

Search the Web now Money-saving coupons


 

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:: 716-674-2818
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   

  

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.

 
Johan Flygare 2
Johan Flygare

This project is significant for many reasons.  The Diamond Blackfan Anemia Foundation (DBAF) is grateful to Diamond Blackfan Anemia Canada (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 fund $10,000 of this $50,000 project. This first collaboration between DBAF and DBAC is certain to be just the beginning of many joint ventures.  We are proud to partner with DBAC and look forward to supporting each others' efforts.  Way to go American and Canadian families and friends for joining forces to fund DBA research in Sweden!  


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 RPS19-deficient 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 RPS19-deficient 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 long-term 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 

DBA ladies
 

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!  DBA Adults men

  

 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!) 


Take the Challenge ~ Show Us Your Logo 

Amelia hot air balloon

 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!  

 

  Here's the challenge:  we'd like to see how  many places we caDBAF  Logon 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  

Ellen Muir

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! 


DBA Fact #5 
What you should consider before SCT (stem cell transplantation/ bone marrow transplant): 

 

 Decide what your reasons are for transplant. Is it 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 (877-DBA-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 
 
Steve Ellis
Steven R. Ellis, PhD
Research Directo

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 and important as the 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, "Ribosome-Mediated 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 Anemia-associated 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;116:2826-2835.

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.