Download Aplastic anemia

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● ● ● CLINICAL TRIALS AND OBSERVATIONS
Comment on Issaragrisil et al, page 1299
Aplastic anemia: what’s in the
environment?
---------------------------------------------------------------------------------------------------------------Judith C. W. Marsh
ST GEORGE’S HOSPITAL, LONDON
The largest and most comprehensive study on the epidemiology of aplastic anemia
is reported by Issaragrisil and colleagues, which identifies new environmental risk
factors for aplastic anemia in Thailand.
espite advances in our understanding of the
pathophysiology of aplastic anemia, the
possible causes of aplastic anemia have proved
more difficult to ascertain and most cases (70%80%) are still considered to be idiopathic.1 Because aplastic anemia is a rare disease, only large
national and international prospective studies
will provide meaningful data on the etiology of
this condition. The incidence in the West is
about 1 to 2 per million per year, but it occurs
more commonly in the Far East, with a 2- to
4-fold higher incidence. Reasons for this striking
difference in incidence are unclear.
In this issue of Blood, Issaragrisil and colleagues
report on a case control study that enrolled 541
patients with aplastic anemia and 2261 control subjects from urban and suburban regions of Bangkok
and the rural areas of Khonkaen and Songkla in
Thailand. Previously reported risk factors for aplastic anemia were also observed in this study, such as
exposure to benzene and other solvents and medical
drugs, namely sulphonamides, thiazides, and mebendazole. For nonsteroidal anti-inflammatory
drugs, the relative risk was increased but was not
significant. There were too few exposures to
chloramphenicol to exclude an increased risk.
No association was found with household pesticides, although a previously reported study from
the United Kingdom identified chemical treatment of houses, particularly for woodworm, as a
significant risk factor.2
Farming practices in rural Thailand revealed
important associations with aplastic anemia.
Significant associations were observed with agricultural pesticides, namely organophosphates,
DDT, and carbamates. Exposure of farmers to
ducks and geese was also a significant risk factor.
A borderline association was observed with animal fertilizer; in contrast, there was no association with chemical fertilizer.
Evaluation of sources of drinking water revealed differences between rural and urban areas of
Thailand. In rural Khonkaen, where most cases
D
1250
and controls used water from nonbottled sources,
there was a significant association with the use of
drinking water from nonbottled sources, which was
not observed in Bangkok. There was also a significant association with nonmedical needle exposure.
Surprisingly, posthepatitic aplastic anemia occurred very infrequently, in a part of the world
where viral hepatitis is endemic. In the West, posthepatitic aplastic anemia accounts for up to 10% of
all cases.
On the basis of these new findings, the
authors propose that an infectious agent may
account for many cases of aplastic anemia in
rural Thailand. Alternatively, chemical contamination of nonbottled water may be a factor. The low drug attributability of aplastic
anemia is confirmed from their previously
reported studies,3 and the current view is that
the risk of aplastic anemia with chloramphenicol
was probably previously overestimated. In contrast, the high etiologic fraction accounted for by
these novel environmental factors should stimulate further research into identifying possible
infectious agents and genetic factors, which may
help to explain the difference in incidence and
etiology of aplastic anemia in the Far East compared with the West. ■
REFERENCES
1. Young NS. Acquired aplastic anemia. Ann Intern Med.
2002;136:534-546.
2. Muir KR, Chilvers CED, Harriss C, et al. The role of
occupational and environmental exposures in the aetiology
of acquired severe aplastic anaemia: a case control investigation. Br J Haematol. 2003;123:906-914.
3. Issaragrisil S, Kaufman DW, Anderson TE, et al. Low
drug attributability of aplastic anemia in Thailand. Blood.
1997;89:4034-4039.
● ● ● HEMATOPOIESIS
Comment on Saito et al, page 1366
The
story of hungry macrophages
---------------------------------------------------------------------------------------------------------------Emmanuel N. Dessypris
McGUIRE VETERANS ADMINISTRATION MEDICAL CENTER
Hemophagocytic syndrome is a disorder characterized by fever, hepatosplenomegaly, pancytopenia, and the presence in the bone marrow, lymph nodes, liver,
and spleen of macrophages that have phagocytized red cells, erythroblasts, platelets, or other hematopoietic cells.
emophagocytic syndrome is part of fatal
primary Epstein-Barr virus (EBV) infection that occurs in children with X-linked lymphoproliferative disorder and familial hemophagocytic lymphohistiocytosis. The former is
associated with mutations in the SAP/SH2D1A
gene that results in abnormal T-cell activation
specific to EBV infection and the latter with either mutation of perforin 1 gene (PRF1), or the
UNC13D gene leading to defective granule exocytosis, or mutations of the STX11 gene associated with abnormal intracellular trafficking. In
both diseases there is an abnormal production of
T helper 1 (Th-1) cytokines leading to macrophage activation.1,2
In adults, the hemophagocytic syndrome
is associated with a variety of viral, bacterial,
H
and parasitic infections, autoimmune disorders, and lymphomas, predominantly of the
T-cell type. In all these conditions, there is
an uncontrolled T-cell activation, with overproduction of Th-1 cytokines as well. In
sporadic cases of EBV infection associated
with the hemophagocytic syndrome, it has
been shown that EBV late membrane protein 1 suppresses the transcription of normal
SAP/SH2D1A.3
In this issue of Blood, Saito and colleagues
describe the first in vitro observation of hemophagocytosis in cultures of CD34⫹ cells in
the presence of thrombopoietin and tumor
necrosis factor-␣ (TNF-␣). Under these conditions the number of generated megakaryocytes decreased with appearance of monocytic
15 FEBRUARY 2006 I VOLUME 107, NUMBER 4
blood
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cells having the immunophenotype of dendritic cells. These dendritic cells were in close
association with developing megakaryocytes
and contained CD61⫹ intracellular material
indicative of phagocytosis of megakaryocyte
cytoplasm. In addition, these dendritic cells
were capable of activating autologous T lymphocytes in vitro. They went further to investigate the type of phagocytic cells in bone
marrow smears from patients with the hemophagocytic syndrome and identified a significant
percentage of these cells as having the immunophenotypic characteristics of dendritic cells.
Previous work by the same group has shown
phagocytosis of immature erythroid cells by dendritic cells in cultures of CD34⫹ cells in the presence of erythropoietin (EPO) and TNF-␣.4
These observations shed more light on the
role of dendritic cells in the hemophagocytic
syndrome, in particular their contribution to
the process of hemophagocytosis and its
propagation through further activation of autologous T lymphocytes. In addition, they raise the
possibility that dendritic cells with phagocytic
activity may contribute during their development in the bone marrow to the development of
tolerance to molecules released from dying or
damaged hematopoietic cells. ■
REFERENCES
1. Coffey AJ, Brooksbark RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative
disease results from mutations in an SH2-domain encoding
gene. Nat Genet. 1998;20:129-135.
2. Stadt UZ, Beutel K, Kolberg S, et al. Mutation spectrum in
children with primary hemophagocytic lymphohistiocytosis:
molecular and functional analysis of PRF1, UNC13D, STX11
and RAB27A. Hum Mutat. 2005. In press.
3. Chuang HC, Lay JD, Hsieh WC, et al. Epstein-Barr
virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood. 2005;106:3090-3096.
4. Fukaya A, Xiao W, Inaba K, et al. Codevelopment of
dendritic cells along with erythroid differentiation from
human CD34⫹ cells by tumor necrosis factor-␣. Exp Hematol. 2004;32:450-460.
● ● ● NEOPLASIA
Comment on Ge et al, page 1570
genes located on chromosome 21. One of
these genes, bone marrow stromal cell antigen (BST2) was chosen for further study
because previous reports have suggested
that bone marrow stromal cells exert a protective effect on leukemic cells. BST2 expression was reduced 8.5-fold in the DSAMKL group. Using multiple approaches,
Ge et al confirmed that BST2 is a bona fide
GATA-1 target gene and showed that fulllength GATA-1, but not GATA-1s, could
efficiently activate BST2 transcription in
vivo. Next, they demonstrated that ectopic
expression of BST2 in a DS-AMKL cell
line, which does not endogenously express
this gene, resulted in a significant reduction
in ara-C–induced apoptosis when cells were
cocultured with bone marrow stromal cells.
Thus, restoration of BST2 expression likely
facilitated an association with the stromal
cells, leading to protection from ara-C–induced cytotoxicity. Decreased expression of
BST2 in DS-AMKL may act in conjunction
with alterations in expression of genes that
govern the metabolism of ara-C, such as cytidine deaminase,3 to elicit the remarkable
Up
and down in Down syndrome: AMKL
---------------------------------------------------------------------------------------------------------------John D. Crispino
UNIVERSITY OF CHICAGO
Children with Down syndrome (DS) show a remarkable predisposition to develop
acute megakaryocytic leukemia. In this issue of Blood, Ge and colleagues identify a set
of genes that are differentially expressed in DS versus non-DS megakaryocytic leukemias. These findings may help explain many of the unique features of DS malignancies.
t is well established that children with
Down syndrome are at an elevated risk of
developing leukemia.1 In particular, the risk
of acute megakaryocytic leukemia (AMKL)
in children with DS is increased 500-fold
over that of children without DS. It has become clear in the last 10 years that DS children with acute myeloid leukemia (AML)
have a significantly better outcome than
non-DS children with AML, with eventfree survival (EFS) approximating 70% to
80%.2 This improved outcome has been
attributed to the increased sensitivity of DS
megakaryoblasts to cytosine arabinoside
(ara-C) therapy.3
In addition, AMKL patients with DS,
but not those without DS, harbor somatic
mutations in the X-linked hematopoietic
transcription factor GATA-1.4 In all patients, the mutations lead to loss of fulllength GATA-1, but persistent expression
I
blood 1 5 F E B R U A R Y 2 0 0 6 I V O L U M E 1 0 7 , N U M B E R 4
of a shortened isoform, GATA-1s, that lacks
the N-terminal transactivation domain.
Thus, it is likely that these mutations contribute to leukemia by leading to altered
expression of GATA-1 target genes. The
identification of these genes that are misexpressed in DS-AMKL blasts is an essential
step in understanding the mechanism of
leukemogenesis in DS.
In order to determine the effect of
GATA1 mutations and trisomy 21 on gene
expression in AMKL, Ge and colleagues
performed gene expression profiling of
leukemia samples from DS and non-DS
children with AMKL. Using Affymetrix
U133A microarray chips, they identified 551
differentially expressed genes, consisting of
105 genes overexpressed in the DS group
and 446 genes in the non-DS group (see figure). Of note, these genes were widely localized to different chromosomes, with only 7
Cluster analysis of differentially expressed genes between DS and non-DS megakaryoblasts; chromosomal
localization of genes in cluster analysis. See the complete figure in the article beginning on page 1570.
1251
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2006 107: 1250a-1251
doi:10.1182/blood-2005-11-4675
The story of hungry macrophages
Emmanuel N. Dessypris
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