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Blood, 1 February 2001, Vol. 97, No. 3, pp. 585-586
Telomerase and T-cell function
Most human cells express insufficient telomerase to
compensate for the loss of telomere repeats that invariably follows DNA replication. As a result, telomeres shorten with age and in
most cells with accumulated cell divisions. These and other findings have made the role of telomerase and telomere shortening in aging a hot
research topic. Of particular interest are the cells of the immune
system. Antigen-specific T and B cells need to respond rapidly to
antigenic challenges, and multiple responses involving many cell
divisions may be required over a lifetime. If the replicative potential
of lymphocytes were limited by progressive telomere shortening, immune
function could eventually be compromised. Previous studies by Norrback
et al (Blood 88:222-229) and Weng et al (Proc Natl Acad Sci U S A
94:10827-10832) showed that certain B cells appear to prevent
progressive telomere shortening by expressing high levels of
telomerase. The situation with T cells is not so clear. While the
overall telomere length in lymphocytes clearly decreases with age (see
Rufer et al, J Exp Med 190:157-167), specific subpopulations involved
in normal immune responses have not been studied in detail. In this
issue Plunkett et al (page 700) studied the telomere length in
antigen-specific T cells during acute infection with Epstein-Barr virus
(EBV). For these studies they combined tetramer staining to identify
EBV-specific CD8+ T cells with fluorescence in situ hybridization (flow
FISH) to measure telomere length. Interestingly, no significant
telomere shortening was observed in antigen-specific T cells during
acute infection and up to one year thereafter. But at later time
points, substantial telomere shortening was observed. These results
suggest that telomerase may postpone but not prevent replicative
telomere shortening in at least some CD8+ T cells. Further
studies are needed to determine whether telomere shortening in T
cells has biologic consequences and to elucidate whether telomere
shortening is delayed in all T cells or only in those cells that
express high levels of telomerase.
 Peter M. Lansdorp
Terry Fox Laboratory
Origin and clinical significance of the TEL/AML1
fusion
Eguchi-Ishimae and colleagues (page 737) report that
TEL/AML1 fusion transcripts can be detected in
lymphoblastoid cell lines after exposure to apoptotic stimuli. Their
data support the hypothesis that repair of double strand breaks induced
by apoptotic stimuli may result in chromosomal translocation and fusion
of genes such as TEL and AML1. Furthermore, they
report, using sensitive nested RT-PCR strategies, that a significant
proportion of healthy individuals (8.8%) and cord blood samples
(1.1%) harbor the TEL/AML1 gene rearrangement. It is
suggested that TEL/AML1 gene rearrangements that
occur as a consequence of sublethal apoptotic stimuli may contribute to
the development of leukemia. TEL/AML1 thus joins a
growing list of fusion genes that can be detected in healthy individuals, including BCR/ABL, MLLtandem
duplications, and IGH-BCL2. This report and others like it raise a number of interesting questions.
Does the presence of an oncogenic fusion gene, detected by RT-PCR,
confer an increased risk to develop leukemia? Taken together, the data
indicate that RT-PCR-detectable fusion genes confer a minimal risk of
developing leukemia. The cumulative likelihood that an individual will
harbor at least one RT-PCR-detectable fusion gene is quite high, yet
the overall incidence of leukemia is only about 1 in 100 000 per year
in the general population. On the one hand, this provides some comfort
that we are not all "walking time bombs" and raises questions about
the pathophysiologic significance of RT-PCR-detectable fusion
transcripts and double-strand breaks. On the other hand, RT-PCR
assays may in fact identify individuals at risk for progression to
leukemia, albeit a low risk. This latter possibility has several
important connotations. For example, what obligation do we have to
report or follow up on RT-PCR positivity for a known oncogene in
healthy individuals? At a minimum, investigators engaged in such
analyses should consider design and implementation of studies that
would allow for assessment of relative risk of leukemia based on the
presence of RT-PCR-detectable fusion genes.
D. Gary Gilliland
Harvard Medical School
A new-look IL-4 for ALL occasions
A major problem in treating acute lymphoblastic leukemia (ALL)
is the occurrence of significant side effects as a consequence of
high-dose chemotherapy. Side effects may also be encountered with
otherwise effective biological agents such as interleukin-4 (IL-4) due
to the widespread expression of IL-4 receptors. New forms of therapy
are therefore urgently needed. In this issue, Srivannaboon et al (page
752) take advantage of the fact that there are 2 known types of IL-4
receptors, 1 type (IL-4R /IL-2R ) expressed on ALL cells
(and normal lymphoid cells) and a second type
(IL-4R/IL-13R) expressed in endothelial cells and
fibroblasts and probably responsible for many of the side effects
caused by IL-4 in vivo. By engineering an IL-4 variant that
discriminates between both receptors, the authors have been able to
select IL-4- apoptotic effects on ALL cells. While possible
effects on normal lymphoid cells remain unknown, it is very encouraging
that at least some stimulatory effects on endothelial cells are not
seen with this IL-4 variant. Beyond its own clinical potential, this IL-4 variant highlights the
feasibility of selecting for particular functions of cytokines when
these are mediated by different receptors. Clearly, the combination of
cytokine/cytokine receptor structure-function analyses and determination of what types of receptors and functions are expressed in
different primary cell types offers a powerful approach for the
development of novel second-generation cytokines with unique biologic
properties and clinical usefulness.
Angel F. Lopez
Hanson Centre for Cancer Research
Iron chelation: 2 better than 1?
Breuer et al (page 792) measure for the first time
desferrioxamine chelatable iron (DFI) in serum using a
fluorescein-desferrioxamine probe whose fluorescence is quenched by
iron. This new assay is used in patients with thalassemia major to
study the transfer of iron between the 2 iron chelators deferiprone and
desferrioxamine. The orally active, highly permeable chelator
deferiprone results in an increased level of DFI in serum. This DFI
disappears when intravenous desferrioxamine is given. The authors
hypothesize that deferiprone enters cells and binds iron, which it
mobilizes into serum. This iron, they suggest, is then transferred to
the higher-affinity ligand desferrioxamine, which expedites its
excretion. The "shuttle" effect they propose provides an
explanation for the earlier findings of Wonke et al (Br J Haematol
103:361-364) that simultaneous administration of deferiprone and
desferrioxamine results in an additive or even synergistic increase in
urine iron excretion compared with either chelator given alone. The
metabolic studies of Grady et al (2000, 42nd Annual Mtg of the American Society of Hematology, Abstract 2594) have also shown that, when the 2 drugs are given simultaneously, there is a synergistic increase in
urine and fecal iron excretion to 2.4-3.4 times that when
desferrioxamine is given alone. Combined therapy should result in better compliance by patients
with self-administered desferrioxamine infusions if they need these
only on 1 or 2 days per week, rather than the current 5 to 7 days per week. Moreover, daily oral deferiprone therapy, which alone is
insufficient in some patients to achieve negative iron balance, may
well achieve this with the additional boost from 1 or 2 days of
desferrioxamine. Combined therapy may also allow doses of both drugs
sufficiently low to avoid side effects. Also, deferiprone may, by
entering cells, rapidly remove from vital organs (eg, the heart) iron
that is then rapidly excreted with the aid of desferrioxamine. The side
effects of both drugs are now reasonably well established. Vigilance,
however, will be needed in patients receiving chelator combinations,
and so long-term clinical trials are needed to test the efficacy and safety of combination therapy of desferrioxamine and deferiprone or of
any other combination of new iron chelators still to be introduced into
clinical practice.
Victor Hoffbrand
Royal Free Hospital
ITP and H pylori: an unexpected association
Emilia et al (page 812) describe a potential association
between Helicobacter pylori infection and idiopathic
thrombocytopenic purpura (ITP). This is intriguing because it may
provide both a clue to the etiology of ITP, as well as a simple and
safe treatment option. Thirteen of 30 patients with ITP were documented
to have H pylori infection; treatment for 1 week eradicated
the infection in 12 of 13 patients, and 6 of the 12 then had an
increased platelet count, some to sustained normal values. The
implication of this observation is that chronic H pylori
infection may be involved in the etiology of ITP in some
patients. The appeal is the simplicity and safety of potential treatment. The goal of treatment for patients with ITP is to prevent
bleeding. No treatment is the appropriate management for patients with
moderate thrombocytopenia and negligible risk for bleeding. When
thrombocytopenia is severe and symptomatic, current treatment options
are limited: glucocorticoids uncommonly result in durable remissions
and their side effects are intolerable, splenectomy has risks and may
only be effective in one half to two thirds of patients, and more
intensive immunosuppression has greater risks. Thus, observations such
as this are immediately attractive. Should this observation change our
practice? Why not? The costs and risks are minimal. But we cannot yet
be confident that this observation will be reproducible; even if it is
true and reproducible, we cannot yet be certain that H
pylori eradication will help the patients with severe ITP who most
need help. But this observation does provide a sound basis for a
systematic study of consecutive patients with ITP to determine whether
H pylori infection truly is a common coexisting condition
and whether eradication of H pylori alters the clinical
course of ITP.
James N. George
The University of Oklahoma
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