Issue #8
May 2011
In This Issue
It's Easy to Help
Out of This World
Show Us Your Logo!
Happy Mom's Day
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.
Where Are You Now?
DBAF Journal Club
It's Easy to Help
Out of This World
by Joanne Drew
Most of us are familiar with the wonderful work the
United Way does in our communities. One thing you
may not be aware of is that the United Way is
broken down into local, individual United Way
chapters. Many of these local chapters give
501(c)(3) organizations like the Diamond Blackfan
Anemia Foundation, the opportunity to apply to their
Directed Donor Program (if offered). This program
would allow for company payroll deduction donations
to be directed to the DBAF minus a nominal
administrative fee.
Photo courtesy of Amy Parrish Photography
My good friend was telling me the other day what activities
and camps she was signing her kids up for this summer. I
didn't admit to her that I hadn't even thought of what my
kids would do this summer. I hadn't because when I plan
The Directed Donor Program provides our DBA
ahead, I think of Fred's follow-up appointments and labs
families an easy way to enable friends, relatives,
and tests and hospital stays and transfusion days.
and co-workers to donate to the DBAF through their
Everything else in our lives fills in around that. In this way,
company's payroll deduction giving programs. To
living with DBA makes us unlike most everyone we know.
date, the DBAF participates in over 15 Directed
Donor Programs around the country. We are hoping And then, aside from how we live with it practically, Mark
and I have this constant awareness in the back of our
to add more chapters to our growing list. To
minds of the side effects of DBA; the iron overload, and
accomplish this, we need your help!
infection, or eye problems, ear problems, heart problems,
growth issues, temper tantrums in the grocery store due, in
part, because of low hemoglobin, blood reactions, the
thought of BMT, and of course we remember with love
those of us who have already earned their angle wings.
Please contact your local United Way Office or
These things press on us like a big older neighbor-kid
representative and ask if they offer a Directed Donor
pushing on a bruise.
Program, or a program they have created, to allow
for directed donations. If they do, please contact the
DBAF and we will assist in completing the
application. Each chapter has their own
requirements and application process.
Editor's note: The DBAF also participates in many
state and federal combined appeal campaigns.
Please contact your local United Way and
ask if they have A Directed Donor
Program today!!!
Upcoming Events
Garage Sale for DBA
May 14, 2011
502 Rebel Drive
Tupelo, MS
Contact:
Victoria Boatman
vjboatman@gmail.com
662.322.4738
DBA 5K Walk/Run
May 21, 2011
Republic Parks & Recreation Center
Republic, MO
Contact:
Jacob & Scarlett Buckmaster
dbabenefit@att.net
417.693.1079
Fun Day for DBA
June 25, 2011
396 Wilson Street
Clinton, MA
Contact:
Matthew Pulnik & Julie Grady
julie.grady@comcast.net
978.733.1609
Friends of DBAF Golf
Outing & Silent Auction
September 17, 2011
Cherokee Hills Golf Club
This is one side of DBA that we all know. But there is
another side of DBA whose effects I am actually glad for
and very proud of. For one thing, Fred has a sense of
empathy and strength that I think have come solely from
his experiences with DBA. He philosophizes about things.
A couple of weeks ago while driving home from our last
hospital stay, Fred said to me: "The thing about anger is, it
doesn't last forever." I turned down the Wiggles song we
were listening to and did a double take! Did that really
come from my 5-year-old? Days later when Matilda cried
about getting her vaccinations, Fred told her, "What does
Snow White do when she's scared? She sings!" And he
sang to her. And then a couple days ago, Dawn and I
were talking on the phone and I said (sort of half joking, but
sort of not) that I felt that Fred would probably never have
issues with teenage drinking because he can't stand the
smell of the alcohol wipes and because it's what the lab
techs and nurses and doctors' hands smell like when they
come near him.
But what strikes me most is that Fred has earned a very
unique perspective on life. He loves space and idolizes
astronauts, partly I suppose because they are cool, but
mostly because he identifies with astronauts in a very real
way. He knows that before astronauts go into space they
have to go to doctors appointments and have a lot of
needle sticks and medical tests. He knows that John Glenn
had his blood drawn ten times while he was on the
Discovery Mission and that he was hooked up to a special
monitor every night while he slept. He has seen the movie
Apollo 13 where Tom Hanks, portraying Jim Lovell, gets so
frustrated with the biosensors taped to his skin that he rips
them off his chest midflight. Fred even knows about
"Astronaut Anemia," a condition in which, in zero gravity,
the bone marrow stops making red cells. Because of these
things so much like his own, Fred believes that going into
space is not only possible in his life experience, it is
inevitable; like learning to tie his shoes and write his name.
This is the essence of Fred's faith. And it has been Fred's
big lesson to Mark and me: just as we have no doubt that
one day he will write his name, we have faith that one day
he will no longer battle DBA.
We had the honor two weeks ago of meeting with John and
Annie Glenn. It was a huge thrill for all of us. And toward
Valley City, Ohio
Contact:
Jim and Carol Mancuso
c-mancuso@sbcglobal.net
ONGOING:
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
the end of our visit Annie said to me, "I can see that you
are very good parents." She meant it honestly and coming
from her it was the single best compliment I think I have
ever had. And I realize writing this, that yes, we are very
good parents. All of us. All of us who live with DBA are very
good parents, indeed.
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.
Led by the artistic talents of
Trevor Mancuso, our DBA families put their hands and
hearts into this project. This beautifully decorated
bookcase was created at Camp Sunshine 2010. Look
closely, our skillfully hand-painted logo adorns the top
shelf. Thanks for the memories Camp Sunshine! Great job
Trevor and campers!
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.
Happy Mother's Day
DBA Cookbooks Available
Contact:
Betty Lightner
betty.lightner@gmail.com
To download your order form:
http://issuu.com/bhivemom/docs/cookbook_order_f
orm-pdf
The Diamond Blackfan Anemia
Foundation extends our sincerest
wishes to all the extraordinary
moms, grandmothers, aunts,
sisters, friends, and all the special
women who touch the lives of our
DBA families. We recognize and
applaud the most difficult and most rewarding job you do.
Do you know about our Mother's to Father's Day
Challenge? Click here to learn more Celebrate DBA
Moms & Dads.
Where Are You Now?
Help us to help you! Some information is best delivered to
your home address. We are currently in the process of
verifying our patients' and families' contact information. If
you have not yet done so, please take a moment to visit
our secure website and complete the registration form.
This information will allow us to keep you updated and
informed.
Thank
you
for
your
cooperation.
http://www.dbafoundation.org/registration.php
If you have any questions regarding the status of your
information, please contact Dawn Baumgardner at
DBAFoundation@juno.com.
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/diamondblackfan-anemia-foundation-dbaf
Quick Links
Make a Donation
Our Website
Join the DBA Yahoo Group
Journal Club
This month's Journal Club is, in
part, a literary piece including a
biography of one of the authors
of the manuscript under
consideration. This biography
will be in the Hellenist tradition,
focusing on big picture items,
rather than a detailed chronology
of a person's life. Is this
biography of one of the elder
Steven R. Ellis, PhD
statesmen (or women) in the
Research Directo
DBA field? Actually not, this
person is in his late 20's early
30's max, but has already
accomplished much at this young age. The subject of this
biography is Dr. Johan Flygare, physician/scientist by
choice, Swede by birth. When I entered the DBA field in
the mid 2000's, Johan was already making a name for
himself as a graduate student in Dr. Stefan Karlsson's lab
at Lund University in Sweden. Their group had created
one of the more sophisticated cellular models of DBA.
During this period, Johan also spent a brief period in my
laboratory and together with Dr. Anna Aspeci, who was
visiting from Irma Dianzani's lab in Italy, we were able to
show a ribosome biogenesis defect in cells from DBA
patients. In the late 2000's Johan had to return to clinical
training, but after receiving his MD he returned to the
Karlsson lab briefly before entering the laboratory of Dr.
Harvey Lodish at the Whitehead Institute in Boston. It is a
manuscript stemming from his time in the Lodish lab that is
the subject of this Journal Club. This manuscript has
substantial implications for the development of improved
therapies for Diamond Blackfan anemia.
:: 716-674-2818
The manuscript (Flygare et al) published in Blood (2011)
117:3435-3444 is entitled "HIF1α synergizes with
glucocorticoids to promote BFU-E progenitor selfrenewal". As you are all aware, steroids are a therapeutic
option for DBA, but come with a number of potential
complications. The work by Flygare and colleagues shows
that drugs that increase the amount of the protein HIF1α
work together with glucocorticoids to stimulate the
production of erythorid progenitor cells found in reduced
amounts in DBA patients. These studies suggest that it
might be possible someday to treat DBA with reduced
steroid doses, or eliminate exogenous steroids altogether
using drugs that increase HIF1α levels. Much still remains
to be worked out before this approach will translate to the
clinic, but it is encouraging to note that drugs targeting HIF
prolyl hydroxylases are currently being considered as
alternative treatments for EPO-responsive anemias so their
toxicity profiles and other pharmacological properties are
currently being examined (Muchnik & Kaplan).
Let us turn our attention back to the Flygare manuscript.
The study begins by describing a new technique to isolate
the hematopoietic progenitor cell populations thought to be
primarily affected in DBA. They were then able to show
that it is the BFU-E progenitor cells that are responsive to
glucorticoids, stimulating their self renewal and thereby
increasing the amount of erythroblasts that can be derived
from individual BFU-Es approximately 40-fold. To
understand how glucocorticoids were having this effect,
Flygare and colleagues examined changes in gene
expression induced by glucocorticoids. Somewhat
surprisingly, the authors found that many of the genes
upregulated by glucocorticoids contained DNA sequence
signatures characteristic of genes regulated by the protein
HIF1α. HIF1α regulates gene expression in response to
low oxygen concentrations. A role for HIF1α in
erythropoiesis has been known for some time as a
regulator of erythropoietin (EPO), which makes a great
deal of sense, because if oxygen concentrations are low, a
reasonable response would be to induce erythropoietin
expression and make more red blood cells. HIF1α itself is
regulated by a family of enzymes known as HIF prolyl
hydroxylases, which use molecular oxygen to label the
HIF1α protein for degradation. When oxygen partial
pressures are low, the HIF prolyl hydroxylases targeting
HIF1α are inhibited, leading to higher levels of HIF1α which
in turn stimulate erythropoietin production. The surprise in
the Flygare manuscript however, was that HIF1α also
appears to be involved in inducing erythropoiesis at an
earlier stage upstream of EPO, acting on BFU-E's to
stimulate their self-renewal.
The authors reasoned that by inhibiting the HIF prolyl
hydroxylases targeting HIF1α they could potentially
increase HIF1α levels and stimulate erythropoiesis at the
progenitor level. Moreover, they felt that glucocorticoids
and prolyl hydroxylase inhibitors might work together or at
least show some partial overlap in stimulating
erythropoiesis at the progenitor stage. When put to the
test, they were able to show that a drug targeting HIF prolyl
hydroxylases enhanced the effect of glucocorticoids in
stimulating BFU-E's by about 7 fold. Thus, the two drugs
have a synergistic effect in inducing the production of CFUE's and erythroblasts from BFU-E's.
What has all this to do with DBA? Plenty, in fact. To quote
the authors, "A group of patients who directly could benefit
from the CFU-E-promoting effect of PHIs [Prolyl
Hydroxylase Inhibitors] are those with the red cell
progenitor disorder DBA." The results from Flygare et al.
suggest that with the synergistic effect seen with prolyl
hydroxylase inhibitors it may be possible to reduce steroid
concentrations in treating DBA patients or possibly
eliminate exogenous steroids altogether through the ability
of prolyl hydroxylase inhibitors to synergize with
endogenous levels of steroids found in DBA patients.
So is there a downside to all of this? Well, yes; inhibiting
prolyl hydroxylases that target HIF1α for degradation could
lead to an enhanced risk of cancer. Once marked for
degradation by prolyl hydroxylases, another protein is
necessary to direct the actual degradation of HIF1α. A
genetic deficiency of this other protein leads to von HippelLindau syndrome, a strong cancer predisposition
syndrome. The rationale for this increased incidence of
cancer is in part, that tumors are frequently hypoxic
(reduced oxygen supply) and need HIF1α expression to
counteract the hypoxia. Thus, promoting HIF1α expression
by using prolyl hydroxylase inhibitors could in principle lead
to an increased risk for cancer. While there is certainly
cause for proceeding with caution on the potential use of
prolyl hydroxylase inhibitors as a treatment option for DBA,
these studies nevertheless open a new window of
opportunity for improved treatment options for patients with
DBA.
One final note in this rather lengthy journal club is that Dr.
Flygare has been supported by the DBA Foundation at
various points in his career. He is transitioning from the
Lodish lab to begin his own laboratory at the same Institute
as that of Stefan Karlsson in Lund Sweden. One of the
proposals currently under review for funding from the DBA
Foundation is from Dr. Flygare as he starts this new phase
of an extremely productive career.
Flygare J, Rayon Estrada V, Shin C, Gupta S, Lodish HF HIF1alpha
synergizes with glucocorticoids to promote BFU-E progenitor selfrenewal. Blood 117(12): 3435-3444
Muchnik E, Kaplan J HIF prolyl hydroxylase inhibitors for anemia. Expert
Opin Investig Drugs 20(5): 645-656