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● ● ● RED CELLS & IRON
Comment on Kusakabe et al, page 1374
c-Maf
rules the island
---------------------------------------------------------------------------------------------------------------Paul A. Ney
NEW YORK BLOOD CENTER
In this issue of Blood, Kusakabe et al make a compelling case that the transcription
factor c-Maf is critical for erythroblastic island formation and fetal erythropoiesis.1
The cell adhesion molecule VCAM-1 is a potential mediator of c-Maf activity.
Erythroblastic islands reconstituted with c-Mafⴙ/ⴙ erythroblasts were immunostained. The number of c-Mafⴙ/ⴙ
erythroblasts surrounding each c-Mafⴙ/ⴙ or c-Mafⴚ/ⴚ macrophage is shown. c-Mafⴙ/ⴙ erythroblasts surrounding
c-Mafⴚ/ⴚ macrophages were significantly reduced as compared with those seen for c-Mafⴙ/ⴙ macrophages. See
the entire figure in the article by Kusakabe et al on page 1374.
he erythroblastic island was ultrastructurally identified as a common organizational
unit of bone marrow more than 50 years ago.2
Erythroblastic islands are composed of erythroblasts, at various stages of maturation, and a
central macrophage. The central macrophage
supports erythroid cell survival and proliferation through intercellular signaling, and facilitates enucleation.3 Along this line, several molecules have been identified that mediate
intercellular attachments and macrophageerythroblast interactions within the island.4-6
Still, despite these advances the role of the
central macrophage in erythroid development
remains somewhat obscure. Kusakabe et al
now show that the basic region-leucine zipper
transcription factor c-Maf is critical for erythroblastic island formation.1,6 The macrophage
is the site of c-Maf activity, and c-Maf deficiency is associated with severe embryonic
anemia and lethality. This study opens a new
avenue into the investigation of erythroblastic
islands.
Establishing the cell type responsible for a
phenotypic effect is challenging and critical in
any study of heterotypic intercellular interactions. Kusakabe et al performed mixing ex-
T
1192
periments with c-Maf– deficient erythroblasts
and macrophages that convincingly show that
defects in erythroblastic island formation,
caused by the loss of c-Maf, reside with the
macrophage.1 However, can the same be said
of the embryonic anemia and lethality, or does
c-Maf deficiency also have an erythroid cell
autonomous effect on development? One approach to address this question is to examine
the effect of c-Maf deficiency on erythropoiesis, when it is induced specifically in the macrophage and erythroid lineages; however, this
requires a conditional Maf-mutant mouse
strain. In lieu of this, 2 other lines of evidence
suggest that c-Maf function in macrophages
and erythroblastic island formation are required for efficient erythropoiesis. First,
c-Maf is expressed in macrophages but not
erythroblasts in the fetal liver, which suggests
that macrophages are the primary site of c-Maf
activity. Second, adult mice transplanted with
c-Maf– deficient fetal liver cells do not develop
anemia. This experiment shows that there is
no cell autonomous requirement for c-Maf in
erythroid development, and further implies
that erythroblastic island function is most im-
portant during fetal development. Alternatively, there may be a fetal-specific requirement for c-Maf in erythroblastic island
formation. Finally, consistent with the proposed role of the central macrophage, Kusakabe et al show that survival of mature c-Maf–
deficient erythroblasts is defective in vivo.1
Thus, c-Maf deficiency causes defective macrophage development and impairs erythroid
cell survival and development through its effect on the erythroblastic island.
Given that c-Maf is the first transcription
factor identified that is important for erythroblastic island function, it raises the question of
the relevant targets of c-Maf in macrophages.
Here, Kusakabe et al provide evidence that
VCAM-1 is one such target. VCAM-1 has a
proven role in erythroblastic island formation,4 which makes it an excellent candidate
for a mediator of c-Maf activity; however, because VCAM-1 is not essential for erythropoiesis, there are likely to be other relevant c-Maf
targets.7 Known regulators of erythroblastic
island formation, such as retinoblastoma and
erythroblast-macrophage protein, have been
excluded; thus, additional targets of c-Maf are
likely to be novel and their identification an
important future objective. Beyond the role of
macrophages in erythroid development,
erythroblastic islands also serve as a paradigm
for interactions between hematopoietic cells
and their microenvironment. In this regard,
the present identification of a transcriptional
regulator of erythroblastic island formation
may lead to broader insights into the regulation of hematopoiesis.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Kusakabe M, Hasegawa K, Hamada M, et al. c-Maf
plays a crucial role for the definitive erythropoiesis that accompanies erythroblastic island formation in the fetal liver.
Blood. 2011;118(5):1374-1385.
2. Bessis M. [Erythroblastic island, functional unity of
bone marrow]. Rev Hematol. 1958;13(1):8-11.
3. Chasis JA, Mohandas N. Erythroblastic islands: niches
for erythropoiesis. Blood. 2008;112(3):470-478.
4. Sadahira Y, Yoshino T, Monobe Y. Very late activation
antigen 4-vascular cell adhesion molecule 1 interaction is
involved in the formation of erythroblastic islands. J Exp
Med. 1995;181(1):411-415.
5. Lee G, Lo A, Short SA, et al. Targeted gene deletion
demonstrates that the cell adhesion molecule ICAM-4 is
critical for erythroblastic island formation. Blood. 2006;
108(6):2064-2071.
6. Soni S, Bala S, Gwynn B, Sahr KE, Peters LL,
Hanspal M. Absence of erythroblast macrophage protein
4 AUGUST 2011 I VOLUME 118, NUMBER 5
blood
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
(Emp) leads to failure of erythroblast nuclear extrusion.
J Biol Chem. 2006;281(29):20181-20189.
7. Ulyanova T, Jiang Y, Padilla S, Nakamoto B, Papayan-
nopoulou T. Combinatorial and distinct roles of alpha5 and
alpha4 integrins in stress erythropoiesis in mice. Blood.
2011;117(3):975-985.
● ● ● TRANSPLANTATION
Comment on Elmaagacli et al, page 1402
CMV:
when bad viruses turn good
---------------------------------------------------------------------------------------------------------------A. John Barrett
NHLBI
Cytomegalovirus (CMV) has had a reputation for causing morbidity and mortality
after allogeneic stem cell transplantation (SCT). In this issue of Blood, Elmaagacli
et al find an unexpected favorable association of a low rate of leukemic relapse in acute
myeloid leukemia patients who reactivate CMV in the first few weeks of SCT.1
Hypothetical mechanisms of a virus-versus-leukemia effect. The myeloid reservoir of latent CMV virus includes
AML blasts that reactivate after SCT. (1) CMV-specific CTLs kill CMV antigen presented by leukemia; (2) CMV
up-regulates LFA-1 in leukemia, increasing susceptibility to NK killing; (3) direct cytotoxic effect of CMV on AML cells.
very now and then retrospective analyses
of SCT data bring up unexpected and
counterintuitive findings. This is the case in
the article by Elmaagacli and colleagues from
the SCT group in Essen, Germany. Analyzing
266 consecutive patients with acute myeloblastic leukemia (AML) who received SCT
from HLA-identical relatives or unrelated
donors between 1997 and 2009, they found an
unusual association between early CMV reactivation and transplantation outcome. Seventy-
E
blood 4 A U G U S T 2 0 1 1 I V O L U M E 1 1 8 , N U M B E R 5
seven patients developing their first CMV
pp65 antigenemia at a median of 6 weeks after
transplantation were found to have a remarkably low risk of leukemic relapse (9% at
10 years after SCT) compared with a 42% risk
in 189 patients not reactivating CMV. Furthermore, they found that, far from being a
risk for increased transplantation-related mortality, the occurrence of CMV reactivation was
not deleterious for survival. In support of a
specific effect of CMV they found that positive
CMV serology in donor or patient was itself
protective against relapse while reactivation of
other viruses had no impact.
Historically, CMV disease has been a major complication of allogeneic SCT.2 In the
days before high-sensitivity monitoring of
CMV antigenemia by PCR for pp65 protein
and preemptive treatment of CMV disease
with ganciclovir or foscarnet, CMV pneumonitis accounted for up to 20% mortality after
transplantation for leukemia.3 Even today,
when death from CMV pneumonitis is rare,
we regard viral reactivation as bad, leading to
CMV disease if not controlled by antivirals,
which in their turn cause cytopenia and renal
damage. CMV reactivation implies immunodeficiency, loss of control of a resident DNA
virus, and breakdown of immunosurveillance
against residual leukemia. The detection of the
virus early after transplantation might be expected to be associated with an increased risk
of relapse. Indeed, an earlier study from the
National Institutes of Health demonstrated
that persisting pp65 antigenemia in the first
3 months after SCT was associated with defective T-cell replication against CMV peptides,
an increased risk of leukemic relapse from the
3-month landmark, and a higher transplantation-related mortality.4
The findings from Elmaagacli et al therefore fly in the face of established perceptions.
Unexpected findings merit special scrutiny if
they are to be validated, and in this article the
authors have gone to extensive lengths to support their conclusions. An obvious confounding factor is that CMV reactivation is closely
linked to the occurrence of acute graft-versushost disease (GVHD), which in turn implies a
graft-versus-leukemia effect; indeed, it has
been suggested that CMV reactivation is a
trigger for GVHD development.5 In this series, grade II-IV acute GVHD doubled the
risk of CMV reactivation and preceded pp65
antigenemia in 90% of cases. However, within
the group of 187 individuals with grade II-IV
acute GVHD, CMV reactivation still had an
independent impact on relapse: in 77 reactivators
the relapse rate was only 9% compared with a
38% relapse rate in 189 nonreactivators. The
same benefit for CMV reactivation held true
for chronic GVHD, considered to be an important long-term control of residual leukemia. In careful multivariate analysis CMV
reactivation remained an independent variable
alongside established risk factors for relapse
1193
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
2011 118: 1192-1193
doi:10.1182/blood-2011-06-359752
c-Maf rules the island
Paul A. Ney
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