From bloodjournal.hematologylibrary.org by guest on September 6, 2011. For personal use only.

2010 115: 3650-3651

doi:10.1182/blood-2010-02-268714

Platelets in bloom
Joel Moake

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 From bloodjournal.hematologylibrary.org by guest on September 6, 2011. For personal use only.

identified high-risk cohorts in adults. This
includes those with t(4;11)(q24.1;q32), t(8;14)
(q24.1;q32), low hypodiploidy, near triploidy,
and a complex karyotype. In contrast, patients
with hyperdiploidy or with a del(9p) had a
significantly improved outcome.6 Molecular
markers in ALL, demonstrated to be of prog-
nostic significance, have mostly been de-
scribed only in the past 5 years. These include
the transcription factor Erg or the expression
of HOX11L2, which are reported to be associ-
ated with an adverse outcome in T-cell ALL.7
It has also been recognized that high BAALC
expression is associated with an inferior prog-
nosis in T-cell ALL.8 Similarly, a Notch1/
FBXW7 mutation was identified in a large
subgroup with a more favorable outcome
among adults with T-lineage ALL.9
The importance of the present report in
this issue of Blood by Kühnl et al is the deter-
mination of a significant molecular prognostic
factor in a large study of more than 350 pa-
tients with B-lineage ALL.1 The high BAALC
expression predicted for a primary resistance
or an overall poor response in the entire cohort
and, most importantly, in the subgroups who
did not express bcr-abl or MLL-AF4. It also
turned out that high BAALC expression oc-
curred significantly more often in older pa-
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Kühnl A, Gökbuget N, Stroux A, et al. High BAALC
expression predicts chemoresistance in adult B-precursor
acute lymphoblastic leukemia. Blood. 2010;115(18):
3737-3744.
2. Rowe JM. Optimal management of adults with ALL.
Br J Haematol. 2009;144(4):468-483.
3. Goldstone AH, Richards SM, Lazarus HM, et al. In
adults with standard-risk acute lymphoblastic leukemia, the
greatest benefit is achieved from a matched sibling alloge-
neic transplantation in first complete remission, and an au-
tologous transplantation is less effective than conventional
consolidation/maintenance chemotherapy in all patients:
final results of the International ALL Trial (MRC UKALL
XII/ECOG E2993). Blood. 2008;111(4):1827-1833.
4. Rowe JM, Buck G, Burnett AK, et al. Induction therapy
for adults with acute lymphoblastic leukemia: results of
more than 1500 patients from the international ALL trial:
MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):
3760-3767.
5. Brüggemann M, Schrauder A, Raff T, et al. Standard-
ized MRD quantification in European ALL trials: proceed-
● ● ● PLATELETS & THROMBOPOIESIS
Comment on Schwertz et al, page 3801
Platelets in bloom
----------------------------------------------------------------------------------------------------------------
Joel Moake RICE UNIVERSITY
ings of the Second International Symposium on MRD as-
sessment in Kiel, Germany, 18-20 September 2008.
Leukemia. 2010;24(3)521-535.
6. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype
is an independent prognostic factor in adult acute lympho-
blastic leukemia (ALL): analysis of cytogenetic data from
patients treated on the Medical Research Council (MRC)
UKALLXII/Eastern Cooperative Oncology Group
(ECOG) 2993 trial. Blood. 2007;109(8):3189-3197.
7. Baldus CD, Burmeister T, Martus P, et al. High expres-
sion of the ETS transcription factor ERG predicts adverse
outcome in acute T-lymphoblastic leukemia in adults.
J Clin Oncol. 2006;24(29):4714-4720.
8. Baldus CD, Martus P, Burmeister T, et al. Low ERG
and BAALC expression identifies a new subgroup of adult
acute T-lymphoblastic leukemia with a highly favorable
outcome. J Clin Oncol. 2007;25(24):3739-3745.
9. Asnafi V, Buzyn A, Le Noir S, et al. NOTCH1/
FBXW7 mutation identifies a large subgroup with favorable
outcome in adult T-cell acute lymphoblastic leukemia (T-
ALL): a Group for Research on Adult Acute Lymphoblas-
tic Leukemia (GRAALL) study. Blood. 2009;113(17):
3918-3924.
10. Gokbuget N, Hoelzer D. Treatment of adult acute
lymphoblastic leukemia. Semin Hematol. 2009;46(1):64-75.

tients, providing another biological reason for
the poor prognosis of ALL with increasing
age. Similarly, high BAALC expression was
significantly associated with a high WBC
count at presentation, once again providing a
more biological rationale for the poor progno-
sis in this group.
Whereas the poor prognosis of patients
with B-lineage ALL, whose cells express bcr-
abl fusion protein or the translocation t(4;11)
(q21;q23) with the MLL-AF4 fusion protein,
has been well established,10 patients lacking
such abnormalities have been considered as
standard risk. And herein lies the challenge.
Without doubt, the most potent antileukemic
therapy for ALL is allogeneic transplantation;
however, its use is limited by the attendant
transplantation-related mortality. The ability
to better define the risk/benefit ratio for indi-
vidual patients is often elusive in the absence
of cytogenetic or molecular determinants. The
report by Kühnl and colleagues, together with
the other known cytogenetic and molecular
prognostic factors, should go a long way to-
ward digging deeper and finally getting closer
to a more biologic classification for adults with
ALL.
Beginning with initial observations a century ago,1 the complex events involved in
platelet production from megakaryocytes have been characterized with increasing
precision during the past decade.2-4 In this issue of Blood, Schwertz and colleagues
add surprising new findings that elucidate the probable terminal event of thrombo-
poiesis, that is, the duplication of human blood platelets.5 Their experiments were
conducted ex vivo in microdrops, as well as in suspension and whole blood cul-
tures. The implication of their report is that platelet replication may also occur in
the circulation and during platelet storage under blood-banking conditions.
ultinucleated megakaryocytes in the ported through the megakaryocyte’s extended
M bone marrow stroma extend long, tubu-
lar cytoplasmic projections (“proplatelets”)
cytoplasmic proplatelet stalks to nascent plate-
let “buds” at the tips of the stalks.2-4 Each ma-
between endothelial cells into the lumina of ture platelet that escapes into the circulation
marrow sinusoids. While anchored to the continues to process its composition of precur-
megakaryocyte within the sinusoids, or after sor mRNAs and to translate the resulting
shear-induced breakage, the proplatelets use functional mRNAs into proteins.6,7 Included
microtubular rearrangements at their tips to among the platelet-translated proteins identified
produce and release mature platelets into the so far are glycoprotein ␣IIb␤3, cyclooxygenase-1
circulation.1-4 These platelets normally circu- and -2 isoforms, components of the spliceo-
late for about 10 days. some complex involved in precursor mRNA
Although devoid of a nucleus and the ca- intron removal, proapoptosis and antiapopto-
pacity to transcribe new mRNA, each platelet sis factors, plasminogen activator inhibitor-1,
produced by this mechanism retains a robust P-selectin, and tissue factor.5-7
capacity to cleave and activate precursor forms In their report, Schwertz et al demonstrate
of mRNA. These precursor mRNAs, previ- that human platelets also retain the essential
ously transcribed in the polyploid nuclei of a molecular components and synthetic capacity
megakaryocyte progenitor, are then trans- that enables them to replicate within a few

3650 6 MAY 2010 I VOLUME 115, NUMBER 18 blood

 From bloodjournal.hematologylibrary.org by guest on September 6, 2011. For personal use only.

ding” (by methods yet to be defined) could be

a novel therapeutic approach to some types of
thrombocytopenia.
The work of Schwertz et al may be use-
ful even sooner in blood banking. Platelets
ex vitro continue the synthesis of proteins for
as long as 10 days.8 Schwertz et al report that
the numbers of platelets also increase over time,
as a consequence of ex vitro platelet “budding,”
and suggest that platelet numbers may in-
crease during platelet storage under blood
banking conditions.5 The authors’ experimen-
tal findings and provocative suggestions are
likely to reinvigorate investigation of methods
to optimize the preparation and “budding” of
stored platelet concentrates.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■

REFERENCES
1. Wright JH. The histogenesis of the blood platelet. J
Morphol. 1910;21:263-277.
2. Geddis AE. The regulation of proplatelet production.
Haematologica. 2009;94(6):756-759.
The “budding” of platelets from proplatelets, and then from mature platelets, during thrombopoiesis. 3. Hartwig J, Italiano J. The birth of the platelet. J Thromb
Megakaryocytes in the bone marrow extend cytoplasmic projections (proplatelets) between endothelial cells Haemost. 2003;1(7):1580-1586.
into the sinusoidal lumen. The proplatelets pinch off their tips to form platelets. In a similar process, a
circulating platelet is capable of extending a thin cytoplasmic projection and transferring some of its metabolic,
4. Dunois-Lardé C, Capron C, Fichelson S, et al. Expo-
granular, and organelle contents into an attached cell body to construct a duplicated new platelet. The dark
sure of human megakaryocytes to high shear rates acceler-
circles in the proplatelets and platelets represent microtubules. (For an example of the platelet replication
ates platelet production. Blood. 2009;114(9):1875-1883.
process, see Figure 1A in the article by Schwertz et al on page 3801.) 5. Schwertz H, Köster S, Kahr WH, et al. Anucleate plate-
lets generate progeny. Blood. 2010;115(18):3801-3809.
6. Weyrich AS, Dixon DA, Pabla R, et al. Signal-
hours (in suspension culture).5 A platelet does How will the study of Schwertz et al relate dependent translation of a regulatory protein, Bcl-3, in acti-
vated human platelets. Proc Natl Acad Sci U S A. 1998;
this by extending a thin cytoplasmic projection to clinical practice? The authors suggest that 95(10):5556-5561.
with a newly forming platelet at the tip of the their observations may explain why, in some 7. Denis MM, Tolley ND, Bunting M, et al. Escaping the
projection. Using this maneuver, a circulating patients, platelet counts are higher than would nuclear confines: signal-dependent pre-mRNA splicing in
anucleate platelets. Cell. 2005;122(3):379-391.
platelet can form a functioning offspring. The be predicted when only few megakaryocytes
8. Thon JN, Devine DV. Translation of glycoprotein IIIa
new platelets are equipped, through the con- are seen in bone marrow samples. It is also in stored blood platelets. Transfusion. 2007;47(12):
necting cytoplasmic projection from the par- possible that augmentation of platelet “bud- 2260-2270.

ent, with organelles (including mitochondria

and its DNA) and ␣-granules—and respond
to thrombin and adenosine diphosphate
(ADP).
It is an initially disconcerting concept that
platelets, unequipped with nuclear DNA, can
produce functional replicas of themselves.
This phenomenon becomes biologically rea-
sonable, however, because circulating platelets
(1) remain active in protein synthesis and
(2) contain the same molecular machinery (dy-
namic microtubules, actin, and myosin) that
allows proplatelets (derived from megakaryo-
cyte cytoplasm) to pinch platelet “buds” from
the tips of proplatelet projections.
A proposed, expanded model of platelet
production that includes the findings of
Schwertz et al is presented in the figure.5
● ● ● RED CELLS & IRON
Comment on Ferrucci et al, page 3810
To be old is to be inflamed?
----------------------------------------------------------------------------------------------------------------
Stanley L. Schrier STANFORD UNIVERSITY
In this issue of Blood, Ferrucci and colleagues continue their important exploration
of anemia in the elderly and its causes.1
long with other groups,2 the authors pre- with a serious increase in morbidity and mor-
A viously reported that the prevalence of
anemia was an astonishing 10% in those older
tality, as well as impaired exercise capacity,
impaired cognition, and a general decrease in
than age 65. But the further surprise was the measurements of quality of life.1 Therefore,
belated recognition that even mild anemia, at correcting this anemia would be a good idea
levels that most hematologists tended to ig- and, as hematologists, it is hoped that we are
nore (hemoglobin ⬎ 110 g/L), was associated taught to do this by identifying and treating its

blood 6 M A Y 2 0 1 0 I V O L U M E 1 1 5 , N U M B E R 1 8 3651