June 2012
In This Issue
Answer That Call!
DBAF Funds More Research and
a Research-rich Conference
Where Are You Now?
Volume 21
The Diamond Blackfan Anemia Foundation(DBAF) is
committed to keeping you updated and connected to the
entire DBA community. The DBA Foundation is YOUR
Foundation! We encourage you to share your ideas, photos,
and stories for our website and upcoming newsletters.
Contact DBAFoundation@juno.com.
Show Us Your Logo!
Journal Club
Answer That Call !
Thanks to YOU...
We did it Again!
DBAF Funds More Research and a
Research-rich Conference
Attn: North American DBA Patients and
Families:
The Diamond Blackfan Anemia Registry
(DBAR) is currently updating the
medical records of DBA patients.
Because there are so few patients, it is
imperative that all North American DBA
patients are registered with the DBAR.
The more accurate and complete
information the DBAR has to analyze,
the more answers we will have to our
many questions. Please help!
Over the summer months, you will be
receiving a phone call from the DBAR.
The DBA Foundation (DBAF) is
proud to announce the funding
of Dr. Fredrick Goldman's
research project
entitled, Toward a cure for
DBA: creation of patientspecific gene corrected
hematopoietic stem cells
using induced pluripotent
stem cell technology. We are
Dr. Fred Goldman
pleased to fund this exciting
project that is on the cutting edge of research and has
the potential to open doors to new and exciting
treatment options for patients with DBA.
The goals of this University of Alabama at Birmingham
research project are (1) to create an in vitro model of
DBA using iPSC (induced pluripotent stem cells) for
The purpose of their call will be to
update your family's information,
including address, e-mail address,
phone numbers, and to collect pertinent
medical data, including current status of
the DBA patient, any new findings or
complications, current medications, as
well as remission statistics and stem cell
transplant outcomes. The DBAR team
thanks you in advance for your
cooperation and willingness to assist
their efforts.
Please note that because of HIPAA
regulations, the Diamond
Blackfan Anemia Registry (DBAR)
and Diamond Blackfan Anemia
Foundation (DBAF) CAN NOT
share information.
You must register with both. To ensure
that your family is receiving the DBAF's
20 page printed newsletter, monthly enewsletters, and other pertinent
materials, please complete the DBA
Foundation's registration form on our
secure website.
On behalf of the DBAR and DBAF,
thank you!
Upcoming Events
DBA Fun Day
June 30, 2012
Clinton, MA
Contact:
Julie Grady
julie.grady@comcast.net
DBA Family Meeting
July 8 - 13, 2012
producing HSC (hematopoietic stem cells) by
reprogramming patient cultured skin fibroblasts and (2)
to use genetic recombination strategy to correct/replace
the gene defect in iPS (induced pluripotent stem) cells
derived from patients with the RPS-19 mutation.
In general, this research may set the stage for an
important patient-specific model system for studying
developmental and physiological aspects of DBA that
are currently unavailable. Such iPS cells could also be
used for drug screening, gene target treatment, and
other purposes. Please see Dr. Steve Ellis's Journal Club
article below for more exciting details.
DBAF is also pleased to announce the sponsorship of
the 9th International Conference on Ribosome
Synthesis to be held in Banff, Alberta, Canada, August
22-26, 2012. The conference brings together world
experts on ribosomopathies and ribosome synthesis.
Diamond Blackfan Anemia will be a major player at the
meeting. This level of attention for Diamond Blackfan
Anemia provides more opportunity for research and
scientific advancement in understanding the disorder.
The third project we are able to fund because of
your generous support, is near
and dear to our hearts. The
DBAF is thrilled to announce
the support of Dr. Steve Ellis'
research support work at the
University of Louisville. Dr.
Steve Ellis' professional and
personal commitment to DBA is
immeasurable and deeply
appreciated. Not only is he our
dedicated Research Director,
Steven R. Ellis, PhD
who is working tirelessly behind
DBAF Research Director
the scenes, he also writes the
DBAF's e-newsletter monthly
Journal Club, and his lab at the University of Louisville
provides research support services to groups from all
over the wold, including Vlachos/Lipton group in New
York, Irma Dianzani, Stefan Karlsson, and most
recently, Ross Fisher, a clinician in San Diego. They
expect to broaden these activities over the next year as
they continue to move forward with a gene discovery
Camp Sunshine
Casco, ME
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
consortium including Drs. Vlachos/Lipton, Bodine, and
Arceci/Farrar. Dr.Ellis's lab is also developing these
strategies as a tool for DBA diagnosis. We are grateful
to Dr. Steve Ellis for the integral role he plays in
researching DBA and in the lives of all DBA patients and
their families.
Friends of DBAF Golf Outing
& Silent Auction
September 15, 2012
Cherokee Hills Golf Club
Valley City, OH
Contact:
Jim & Carol Mancuso
c-mancuso@sbcglobal.net
Ongoing Fundraisers
Family Letter Writing
Campaign
Pre-printed letters and envelopes
have been created for you to send
to your contacts! Call or email for
more information.
Contact:
Dawn Baumgardner
The DBA Foundation sincerely thanks all our families
and friends that have made funding of the research and
conference possible.
Our hope for a cure is research. Your generous
donations and fundraisers allow us to advance our
mission of supporting DBA patients, families, and
research.
Where Are You Now?
The Diamond Blackfan Anemia
Foundation, Inc. strives to keep you
informed. We recently mailed out a
20 page printed newsletter. If you
did not receive your copy, we may
not have your current contact
information. If it was forwarded to
your current address, please provide us with your new
address.
dbaumgardner@dbafoundation.org
716.674.2818
Wristbands Available
In order to best serve you, we need your help. To help keep
our database information current, please complete the secure
registration form on our website.
http://www.dbafoundation.org/registration.php
Contact:
Twila Edwards
twilak@cox.net
Show Us Your Logo!
Matthew Pulnik of Clinton,
MA is an extraordinary young
man! For the third year, he
will be hosting and organizing
a "Fun Day for DBA."
Tribute Cards Available
(2 Styles)
In honor of...
In memory of...
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
716.674.2818
Matthew stated,
"Two years ago I decided to have a Fun Day to raise money for
Diamond Blackfan Anemia. I raised over $1000 in just 3
hours through fun games and raffles and last year I raised over
$2000. It was so much fun I am making it an annual event."
THANK YOU Matthew, family, and friends!
Here's the challenge: We would 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, stick 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.
DBAF's Monthly Journal Club
5" x 5" Decals Available
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
716.674.2818
The latest in an increasingly
long list of genes
responsible for DBA has
recently been published by
Dr. Hanna Gazda and her
colleagues in the Journal of
Clinical Investigation1. Lo
and behold, this is the first
gene for DBA that does not
Steven R. Ellis, PhD
encode a ribosomal
DBAF Research Director
protein. Instead, this gene
encodes GATA1, a
transcription factor
involved in erythroid development. I will have more to say
about GATA1 in subsequent Journals Clubs, but for now what
this finding illustrates is the underlying genetic complexity of
DBA and that they may be alternative pathways leading to the
same disease state. This new finding raises the question of
whether there are different forms of DBA, and if so, whether
finding a cure for one form will be of benefit for another.
One potential cure that may not be dependent on the gene
affected, is the possibility of using gene-corrected patientderived induced pluripotent stem cells (IPSCs) to treat DBA
patients. In an accompanying article in this month's
newsletter, the DBAF has announced funding for Dr. Fred
Goldman which will allow him to create and begin to study
IPSCs from DBA patients.
Cookbooks Available
Contact:
Betty Lightner
betty.lightner@gmail.com
To order online, visit:
Cookbook order form
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shopping online!
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A logical question at this juncture is, "What are IPSCs?" IPSCs
are cells derived from a human subject that are genetically reprogrammed to behave in a manner similar to embryonic stem
cells, which you've probably heard discussed in the news and
many other venues. Embryonic stem cells are cells created
early during human development shortly after an egg is
fertilized. These cells can differentiate into any cell type
within the body and are referred to as being "pluripotent" to
reflect this fact. The idea is that since these cells can
differentiate into any other cell type, it might be possible to
use these cells to replace cells that die either from old age,
virus destruction, or even genetic diseases. There is
considerable controversy around the use of embryonic stem
cells, as they are derived from human embryos and so are
construed by many as destroying human life, and so, morally
objectionable as a therapeutic tool2.
This brings us back to the idea of using IPSCs as a surrogate
for embryonic stem cells. These cells, which can be derived
from cells found in human skin, can be re-programmed in a
test tube back to a state where they behave much like an
embryonic stem cell, and so could potentially be developed as
cellular therapeutics without the same type of ethical qualms
one encounters with embryonic stem cells. Moreover, by
using cells derived from a patient to treat the same patient, it
should be possible to avoid complications that arise from
immunological rejection when transplanting organs or tissues
from one individual to another.
The overly simplistic strategy for employing this technique as
a cure for DBA is to take a patient's cells (let's say skin
fibroblasts), re-program them to IPSCs, correct the underlying
genetic defect, induce these pluripotent cells to become
hematopoietic stem cells, and then transplant the patient with
their own gene-corrected hematopoietic stem cells. The
beauty here is that it really doesn't matter which gene is
affected, as it is just a matter of correcting one gene rather
than another (not that this is a trivial process). Of course, you
must know the gene affected for this strategy to work, so
consider this a shameless plug for ongoing gene discovery
efforts in the DBA field.
So, what's the catch in all this, as it most certainly seems too
good to be true? Well, such skepticism is warranted because at
present there are still considerable obstacles to overcome
before IPSCs become a therapeutic reality. The encouraging
news however, is that because of its promise there are many
groups working in this area on many disease fronts. In this
regard, there are some very interesting papers recently
published on Fanconi anemia field that illustrate where we
may be going in applying this technology to DBA 3.
Join the Yahoo Group
:: 716-674-2818
Fanconi anemia is another inherited bone marrow failure that
differs from DBA in being caused by a defect in DBA repair
rather than ribosome synthesis. Nevertheless, many of the
principles involved in developing IPSCs for therapeutic uses in
Fanconi anemia also apply to DBA. One of the challenges for
creating IPSCs from Fanconi patients is that the reprogramming process tends to activate p53, which also
appears to be activated as part of the disease process. This
double whammy, so to speak, in inducing p53 which in turn
promotes cell death or arrests cell division, appears to reduce
the frequency in which investigators are able to derive IPCSs
from patient samples. We might expect some of the same
challenges for DBA as p53 contributes to the disease process
here as well 4. One strategy used by investigators in the
Fanconi anemia field to get around this problem is to correct
the genetic defect first in patient cells and then convert them
to IPSCs. While this strategy has its own set of challenges, the
paper by Müller and colleagues 3 and the accompanying
commentary 5 illustrate that these challenges can be overcome
and therefore bode well for efforts in creating IPSCs from DBA
patients.
While progress is being made in resolving technical issues
relating to developing IPSCs from certain patient populations,
there are larger, more frightening, issues of safety that will
need to be resolved before therapeutic use of IPSCs will
become a reality. A good review on the promises and
challenges of using IPSCs therapeutically has been published
by Müller, Daley, and Williams 6.
One of the major concerns with IPSCs safety involves the reprogramming process itself. When initially developed, it took
the forced expression of 4 different genes to reprogram
somatic fibroblasts to IPSCs. These genes were introduced
into fibroblasts on viral vectors which integrate randomly into
the human genome. This integration can activate certain genes
or inhibit others and has been linked to cancer induction in
certain gene therapy trials 7. Moreover, one of the four genes
initially used in reprogramming is c-Myc, a major human
oncogene, and so pose a significant cancer risk. It is now
possible to reprogram cells without this oncogene thereby
significantly reducing cancer risk. There are also strategies
being developed to put all of the genes needed for reprogramming on a single viral vector to limit the number of
integration sites and further reduce the cancer risk. Another
cancer risk is that when undifferentiated cells like IPSCs are
injected into animals they create what are known as
tetratomas, undifferentiated cells mass which have tumor like
properties. So strategies are being developed to eliminate
teratoma formation.
Even with reprogramming strategies becoming safer, there are
additional obstacles to making therapeutic IPSCs a reality.
Particularly relevant for DBA, is the fact that so far no one has
been able to figure out how to create transplantable
hematopoietic stem cells from IPSCs. I for one have complete
faith in the creativity of the innumerable minds working on
this problem and do not foresee it remaining a road block for
too long.
Despite the fact that using IPSCs therapeutically in humans
may still be a ways off, having IPSCs for experimental
purposes will be a big boon for DBA research. These cells
could be used to study the molecular underpinnings of DBA or
as tools for drug screens. So let us wish Dr. Goldman all the
best in his studies to create IPSCs from DBA patients, and look
forward to the future and the myriad of ways that IPSCs can
be used to find a cure.
1.
Sankaran VG, Ghazvinian R, Do R, et al. Exome sequencing
identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J
Clin Invest. 2012. Prepublished on 2012/06/19 as DOI
10.1172/JCI63597.
2.
Lo B, Parham L. Ethical issues in stem cell research. Endocr
Rev. 2009;30(3):204-213. Prepublished on 2009/04/16 as DOI
10.1210/er.2008-0031.
3.
Muller LU, Milsom MD, Harris CE, et al. Overcoming
reprogramming resistance of Fanconi anemia cells. Blood.
2012;119(23):5449-5457. Prepublished on 2012/03/01 as DOI
10.1182/blood-2012-02-408674.
4.
Dutt S, Narla A, Lin K, et al. Haploinsufficiency for ribosomal
protein genes causes selective activation of p53 in human erythroid
progenitor cells. Blood. 2011;117(9):2567-2576. Prepublished on
2010/11/12 as DOI 10.1182/blood-2010-07-295238.
5.
Papapetrou EP. FA iPS: correction or reprogramming first?
Blood. 2012;119(23):5341-5342. Prepublished on 2012/06/09 as DOI
10.1182/blood-2012-04-417246.
6.
Muller LU, Daley GQ, Williams DA. Upping the ante: recent
advances in direct reprogramming. Mol Ther. 2009;17(6):947-953.
Prepublished on 2009/04/02 as DOI 10.1038/mt.2009.72.
7.
Baum C, Modlich U, Gohring G, Schlegelberger B. Concise
review: managing genotoxicity in the therapeutic modification of stem
cells. Stem Cells. 2011;29(10):1479-1484. Prepublished on
2011/09/08 as DOI 10.1002/stem.716.