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Blood, 1 January 2001, Vol. 97, No. 1, pp. 1-2
INSIDE BLOOD
CAMT: new findings and new questions
Ballmaier and colleagues (page 139) have identified the
molecular cause of congenital amegakaryocytic thrombocytopenia (CAMT) in 9 patients: deficiency in expression or function of the
thrombopoietin receptor c-mpl. Together with 2 earlier, smaller
studies, this report adds CAMT to the growing list of congenital
disorders of hematopoietic cytokine receptors, such as Laron dwarfism
(growth hormone receptor) and severe combined immunodeficiency
( C chain of the IL-2, IL-4, IL-7, IL-15, and IL-21
receptors). The extensive cellular and molecular evaluation performed
in the study adds to our understanding of the role of thrombopoietin in
hematopoiesis, by verifying in humans important conclusions derived
from studies of genetically engineered mpl-deficient
mice. It is now clear that, like that of mice, the human
thrombopoietin/mpl system is vital for hematopoietic stem cell
function, as these patients have defects in all hematopoietic
progenitors and develop pancytopenia, probably due to stem cell exhaustion. In addition to defining another disease on the genetic level and
extending our physiologic understanding of hematopoiesis, Ballmaier and
colleagues raise a number of very interesting scientific and clinical
questions. Five of the mutations identified by the authors were
frame-shift or nonsense mpl mutations, but the remainder were more subtle. What do the point mutants in the extracellular domain
of mpl tell us about the structure-function relationships of
the receptor? If mpl deficiency can cause CAMT, why have
thrombopoietin mutations not been identified as an etiology? And should
CAMT patients be considered for gene therapy? As CAMT is a severe
disorder that eventuates in aplastic anemia, that can only be treated
by stem cell transplantation, and that requires a low level of gene expression to remedy and as mpl-transduced stem cells will
have an obvious growth advantage in patients, it seems time to add the
disease to the list of candidate diseases for gene therapy.
 Kenneth Kaushansky
University of Washington
Stopping GVHD: suicide versus homicide
The concept of introducing "suicide" genes into cells via
gene-transfer vectors in order to allow subsequent controlled
destruction of the cells was conceived initially as a method to treat
aggressive brain tumors. The prototype suicide gene encodes the herpes
simplex virus thymidine kinase enzyme gene (HS-tk).
Introduction of this gene into target cells renders
them susceptible to specific killing by nucleoside analogs such as
ganciclovir. Bonini, Bordignon, and colleagues reasoned that
introduction of a suicide gene into allogeneic T lymphocytes could be
used to control posttransplantation EBV lymphoproliferation or leukemia
relapse but allow destruction of the cells if significant GVHD
occurred. Their 1997 pioneering study reported encouraging data in 3 patients receiving DLI after transplantation, with evidence for a
graft-versus-leukemia effect and effective control of GVHD with
subsequent administration of ganciclovir. In this issue, Tiberghien and colleagues report on the application of
this concept to a larger group of patients, moving the administration
of HS-tk gene-modified T cells back to the time of initial
allogeneic marrow transplantation (see page 63). This detailed study
illustrates both the clinical potential and the practical difficulties
of this complex technology. Successful transduction and selection of
HS-tk T cells from 12 donors was documented, and circulating
gene-modified cells were detectable in all patients after
transplantation. Three-quarters of patients with significant acute or
chronic GVHD were treated successfully with ganciclovir alone,
accompanied by reduction in the number of circulating gene-modified T
cells. But it was of concern that 3 of 12 patients developed
posttransplantation EBV lymphoproliferation, suggesting that the
prolonged ex vivo culture period necessary to allow transduction and
selection of HS-tk donor T cells may have compromised
function of these cells. Future studies will be needed to explore
alternative transduction and selection approaches and suicide genes. In
the setting of alternative donor transplants, the ability to deliver a
"designer" graft containing optimal stem cell numbers along with T
cells able to facilitate engraftment and deliver a graft-versus-tumor
effect but also sensitive to killing via a suicide gene is very
attractive, especially as an alternative to high-dose systemic
immunosuppression, which is often ineffective in treating
established severe GVHD.
Cynthia Dunbar
National Institute of Health
The soluble  c cytokine receptor subunit: theme and
variation
The cytokine receptor molecular family members demonstrate a
particular propensity to exist in both anchored and soluble forms. In
this issue Meißner and colleagues (page 183) provide solid evidence
that the murine c, the subunit common to the receptors for IL-2,
IL-4, IL- 7, IL-9, and IL-15, now joins the growing list of cytokine
receptors that can escape their membrane tether. Their data provides
much insight into the regulated nature of the production of the soluble
c (sc), the structure of the soluble receptor, the biological
impact of sc, and the mechanism by which the soluble isoform arises. The soluble c joins a short list, including soluble gp130 and
soluble  c, of soluble versions of cytokine receptor subunits that
have no intrinsic affinity for ligand. Despite this, Meißner's data
suggests that sc can antagonize the biologic activity of its ligands
by participating in the assembly of the larger cytokine-cytokine receptor complex on the cell surface, presumably usurping the action of
the membrane spanning version of c. Given that other subunits of the
extended IL-2R family are known to exist in soluble forms, there arises
the possibility that a whole series of multisubunit ligand-receptor
complexes assemble in solution each contributing to the modulation of
cellular response. Furthermore, knowing that severe combined
immunodeficiency can arise from loss of function defects of c, one
wonders what role this antagonistic soluble c might play in
immunodeficiency states; a question that provides impetus for a further
understanding of the potentially unique proteolytic mechanisms which
the authors show seem to control the release of c from the cell
surface. Your humble correspondent is left once again amazed at the
diversity that Nature is able to generate from variations on the simple
theme of a cytokine receptor.
Christopher Brown
University of Calgary
Fucose-dependent repair of LADII
The rare leukocyte adhesion deficiency type II (LADII) syndrome
is associated with absence of selectin ligand activity on leukocytes
and defective selectin-dependent leukocyte adhesion. Defective selectin
ligand activity is thought to be consequent to faulty fucosylation of
the glycans that decorate leukocyte selectin counterreceptors and that
are essential to selectin ligand activity. Faulty fucosylation in LADII
has been associated with defects in the constitutive, mannose-dependent
cytosolic pathway for synthesis of the fucosyltransferase substrate
GDP-fucose, or in transport of this molecule into the lumen of the
Golgi apparatus where fucosylation takes place. The fucosylation defect
exhibited by cultured LADII cells may be overcome by growing the cells
in media supplemented with fucose. This maneuver supplies a
fucose-dependent salvage pathway for GDP-fucose synthesis and may also
overcome defects in GDP-fucose transport. In a 1999 Blood
article (Marquardt et al, 94:3976-2935), this approach was tried
in one LADII patient. This individual experienced a restoration of
leukocyte selectin ligand activity and amelioration of infectious
complications following chronic oral administration of fucose. But
these studies could not exclude a noncausal association between
re-expression of selectin ligands and fucose administration. Lühn
and colleagues (see page 330) now extend these studies to demonstrate
that leukocyte selectin ligand expression in this LADII patient is
dependent upon fucose administration. In this study, leukocyte selectin
ligand activity rapidly disappeared when fucose was withheld from the
patient and reappeared following chronic readministration of the
monosaccharide. This work confirms that fucosylation is essential to
selectin ligand activity and to leukocyte trafficking processes
responsible for host defense mechanisms. These studies also support
prior evidence that selectin ligands contribute to homeostasis in blood leukocyte number, since this patient's leukocyte counts varied inversely with selectin ligand expression and serum fucose
concentration. Although these studies further advance our understanding
of the important role for fucosylation in selectin ligand activity,
much remains to be learned about the pathophysiology of this disease and about the genes that control GDP-fucose synthesis. In contrast to
the patient studied by this group, an LADII patient from a different
kindred studied by another group did not respond to oral fucose. The 2 patients appear to exhibit distinct biochemical defects, although it is
not yet clear if these correspond to mutations in the same locus, nor
how these can account for the contrasting therapeutic responses to
fucose. Molecular cloning of the defective locus in these LADII
patients and characterization of the mutant alleles responsible for
defective fucosylation should clarify the situation. These studies,
considered together with several recent reports implicating
fucosylation in the regulation of Notch-dependent signal transduction,
should also eventually shed light on how defective fucosylation may
contribute to the short stature, dysmorphology, and mental retardation
also characteristic of LADII.
John B. Lowe
Howard Hughes Medical Institute
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[Abstract]
[Full Text]
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