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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2629-2640
REVIEW ARTICLE
Cyclical Neutropenia and Other Periodic Hematological Disorders: A
Review of Mechanisms and Mathematical Models
By
Caroline Haurie,
David C. Dale, and
Michael C. Mackey
From the Departments of Physiology, Physics, and Mathematics, Center
for Nonlinear Dynamics in Physiology and Medicine, McGill University,
Montreal, Quebec, Canada; and the Division of Hematology, Department of
Medicine, University of Washington, Seattle, WA.
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ABSTRACT |
Although all blood cells are derived from hematopoietic stem cells,
the regulation of this production system is only partially understood.
Negative feedback control mediated by erythropoietin and thrombopoietin
regulates erythrocyte and platelet production, respectively, but the
regulation of leukocyte levels is less well understood. The local
regulatory mechanisms within the hematopoietic stem cells are also not
well characterized at this point. Because of their dynamic character,
cyclical neutropenia and other periodic hematological disorders offer a
rare opportunity to more fully understand the nature of these
regulatory processes. We review the salient clinical and laboratory
features of cyclical neutropenia (and the less common disorders
periodic chronic myelogenous leukemia, periodic auto-immune hemolytic
anemia, polycythemia vera, aplastic anemia, and cyclical
thrombocytopenia) and the insight into these diseases afforded by
mathematical modeling. We argue that the available evidence indicates
that the locus of the defect in most of these dynamic diseases is at
the stem cell level (auto-immune hemolytic anemia and cyclical
thrombocytopenia seem to be the exceptions). Abnormal responses to
growth factors or accelerated cell loss through apoptosis may play an
important role in the genesis of these disorders.
© 1998 by The American Society of Hematology.
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REGULATION OF HEMATOPOIESIS |
MATURE BLOOD CELLS and recognizable
precursors in the bone marrow ultimately derive from a small population
of morphologically undifferentiated cells, the hemopoietic stem cells
(HSC), which have a high proliferative potential and sustain
hematopoiesis throughout life (Fig 1). The earliest HSC
are totipotent and have a high self-renewal capacity.1-3
These qualities are progressively lost as the stem cells differentiate.
Their progeny, the progenitor cells, or colony-forming units (CFUs),
are committed to one cell lineage. They proliferate and mature to form
large colonies of erythrocytes, granulocytes, monocytes, or
megakaryocytes. The growth of CFUs in vitro depends on lineage-specific
growth factors, such as erythropoietin (EPO), thrombopoietin (TPO),
granulocyte colony-stimulating factor (G-CSF), monocyte
colony-stimulating factor (M-CSF), and granulocyte-monocyte
colony-stimulating factor (GM-CSF).
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| Fig 1.
The architecture and control of hematopoiesis. This
figure gives a schematic representation of the architecture and control
of platelet (P), red blood cell (RBC), and monocyte (M) and granulocyte
(G) (including neutrophil, basophil, and eosinophil) production.
Various presumptive control loops mediated by TPO, EPO, and G-CSF are
indicated, as well as a local regulatory (LR) loop within the
totipotent HSC population. CFU (BFU) refers to the various colony
(burst) forming units (Meg, megakaryocyte; Mix, mixed; E, erythroid;
G/M, granulocyte/monocyte) that are the in vitro analogs of the in vivo
committed stem cells (CSC).
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EPO ajusts erythropoiesis to the demand for O2 in the body.
A decrease in tissue pO2 levels (in response to any one of
a number of factors) leads to an increase in the renal production of
EPO. This, in turn, leads to an increased cellular production by the primitive erythroid precursors (colony-forming
units-erythroid [CFU-E]) and, ultimately, to an increase in the
erythrocyte mass and hence the tissue pO2 levels. This
increased cellular production triggered by EPO is due, at least in
part, to an inhibition of preprogrammed cell death
(apoptosis)4,5 in the CFU-E and their immediate progeny.
Thus, EPO mediates a negative feedback such that an increase (decrease)
in the erythrocyte mass leads to a decrease (increase) in erythrocyte
production.
The mechanisms regulating granulopoiesis are not as well understood.
G-CSF, the primary controlling agent of granulopoiesis, is a completely
sequenced high molecular weight molecule6 produced by a
number of tissues (fibroblasts, endothelial, and epithelial) and
circulating cells (monocytes). G-CSF is absolutely essential for the
growth of the granulocytic progenitor cells colony-forming units-granulocyte (CFU-G) in vitro.7 CFU-G
colony growth is a sigmoidally increasing function of increasing G-CSF
concentration.8,9 One of the modes of action of G-CSF,
along with several other cytokines, is to decrease
apoptosis.7,10-12 Additionally, there is a clear shorting
of the neutrophil maturation time under the action of
G-CSF.13
The important role of G-CSF for the in vivo control of granulopoiesis
was demonstrated by Lieschke et al.14 They showed that mice
lacking G-CSF (due to an ablation of the G-CSF gene in embryonal stem
cells) have pronounced neutropenia and reduction of the marrow
granulocyte precursor cells by a factor of 50%. The administration of
exogenous G-CSF corrects the neutropenia in 1 day and restores the
marrow composition to that typical of a normal wild-type mouse within 4 days. G-CSF also rapidly corrects neutropenia of diverse causes in
humans15-20 and other mammals.21-23
Several studies have shown an inverse relation between circulating
neutrophil density and serum levels of G-CSF.24-27 Coupled with the in vivo dependency of granulopoiesis on G-CSF, this inverse relationship suggests that the neutrophils would regulate their own
production through a negative feedback, as is the case with erythrocytes, in which an increase (decrease) in the number of circulating neutrophils would induce a decrease (increase) in the
production of neutrophils through the adjustement of G-CSF levels.
Although mature neutrophils bear receptors for G-CSF and for GM-CSF,
the role of these receptors in governing neutrophil production is not
yet known.
The regulation of thrombopoiesis presumably involves similar negative
feedback loops. Megakaryopoiesis can be separated in two processes: the
proliferation and differentiation of megakaryocytic progenitor cells,
and the complex process of maturation of precursor cells, which
includes a variable number of endomitotic nuclear divisions,
cytoplasmic growth and maturation, and the development of
platelet-specific structures.
Until recently, the regulation of megakaryopoiesis was thought to
include two separated control mechanisms28,29: first, a
regulatory loop mediated by a megakaryocte colony stimulating antigen
(Meg-CSA) responding to megakaryocyte demand and acting on the
proliferation of colony-forming unit-megakaryocte (CFU-Meg); second, a
thrombocytopenia-activated control of the maturation of megakaryocytes,
mediated by TPO. Several growth factors, such as interleukin-11
(IL-11), IL-6, IL-3, and GM-CSF possess either one (but not both) of
these activities and promote platelet production in vivo. However, none
was found to be specific to the megakaryocytic lineage.28
A lineage-specific factor that is the ligand for Mpl receptor has been
cloned recently that has both Meg-CSA and TPO activity.30 Plasma TPO levels are increased in thrombocytopenic
patients.31 Administration of TPO to nonhuman primates
induces up to sixfold to sevenfold increases in the platelet
counts.31,32 It is now thought that the Mpl ligand mediates
a negative feedback loop regulating platelet production.33
There are more than 15 other cytokines acting on
hematopoiesis,6 with broad, redundant
actions.6,34 In vitro studies have shown that IL-3 and stem
cell factor (SCF; Kit ligand) are involved with the survival of HSC,
whereas IL-6, IL-11, IL-12, and G-CSF have synergestic effects on the
entry into cycling of dormant HSC.17,35 In contrast to the
committed progenitors, the growth of HSC in vitro thus depends on the
interaction of several cytokines. The action of G-CSF on the cycling of
HSC in vitro is supported by in vivo effects. Whereas suppression of G-CSF only affects granulopoiesis,14 G-CSF administration
can result in multilineage recovery36 and modify the
kinetics of colony-forming units-spleen
(CFU-S).37 Little is known about how the self-maintenance
of the HSC population is achieved. HSC are usually in a dormant state
but are triggered to proliferate after transplantation into irradiated
hosts.38 The specific mechanisms regulating the
differentiation commitment of HSC are unknown.39
Self-maintainance of HSC depends on the balance between self-renewal
and differentiation. Mechanisms that could support auto-regulatory
feedback control loops controlling HSC kinetics are starting to be
investigated.40
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PERIODIC HEMATOLOGICAL DISORDERS |
Cyclical Neutropenia (CN)
General features.
CN has been the most extensively studied periodic hematological
disorder. Its hallmark is a periodic decrease in the circulating neutrophil numbers from normal values to very low values. In humans, it
occurs sporadically or as an autosomal dominantly inherited disorder,
and the period is typically reported to fall in the range of 19 to 21 days,41 although recent data indicate that longer periods
occur in some patients.42 Our understanding of CN has been
greatly aided by the discovery that the grey collie suffers from a very
similar disease. The canine disorder closely resembles human CN with
the exception of the period that ranges from 11 to 15 days43 and the maximum neutrophil counts, which are higher
than for humans. For reviews see.41,44-50
It is now clear that in both human CN42,51-53 and the grey
collie,43,54 there is not only a periodic decrease in the
circulating neutrophil levels, but also a corresponding oscillation of
platelets, often the monocytes and eosinophils and occasionally the
reticulocytes and lymphocytes (Fig 2A). The
monocyte, eosinophil, platelet, and reticulocyte oscillations are
generally from normal to high levels, in contrast to the neutrophils,
which oscillate from near normal to extremely low levels. Often (but
not always), the period of the oscillation in these other cell lines is
the same as the period in the neutrophils.
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| Fig 2.
Representative patterns of circulating cell levels in
four periodic hematological disorders considered in this review. (A)
CN,54 (B) PV,55 (C) AA,56 and (D)
periodic CML.57 The density scales are neutrophils,
103 cells/µL; white blood cells, 104
cells/µL; platelets, 105 cells/µL; reticulocytes,
104 cells/µL; and Hb, g/dL.
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The clinical criteria for a diagnosis of CN have varied widely,
although the criteria used by Dale et al58 are widely
accepted. These criteria are that a patient must display an absolute
neutrophil count (ANC) less than 0.5 × 109/L at least 3 to 5 consecutive days per cycle for each of three regularly spaced
cycles. Usually, this requires blood cell counts three times per week
for 6 to 8 weeks. Most patients will also have significant symptoms
(malaise and anorexia) and signs (eg, fever, mouth ulcers, and
lymphoadenopathy) during their neutropenic periods. Sometimes it is
difficult to make the diagnosis with certainty. Using periodogram
analysis, some patients classified as having CN do not in fact display
any significant periodicity, whereas other patients classified with
either congenital or idiopathic neutropenia do display significant
cycling.42
Origin.
Transplantation studies show that the origin of the defect in CN is
resident in one of the stem cell populations of the bone marrow.59-64 Studies of bone marrow cellularity throughout
a complete cycle in humans with CN show that there is an orderly cell
density wave that proceeds successively through the myeloblasts,
promyelocytes, and myelocytes and then enters the maturation
compartment before being manifested in the
circulation.54,65 Further studies have shown that this wave
extends back into the CFU-G,66 CFU-E,67-70 as
well as in the burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte-macrophage (CFU-GM),69,71
suggesting that it may originate in the totipotent HSC populations.
Studies in the grey collie9,72 and in
humans8,73 show that the responsiveness of granulocyte
committed progenitor cells to G-CSF is greatly attenuated in CN
compared with normal. Patients also differ from normal in their
requirements for GM-CSF but not for IL-3.73
In CN, the levels of colony-stimulating activity (CSA-related to G-CSF)
fluctuate inversely with the circulating neutrophil levels and in phase
with the peak in monocyte numbers.74-76 EPO levels
oscillate approximately in phase with the reticulocyte oscillation.75 Dunn et al77 have also shown a
periodic stimulation/repression of CFU-S (the HSC) by conditioned media
derived from cyclic neutropenic marrow. It is unclear if these
correlations and inverse correlations between levels of circulating
cells and putative humoral regulators are related to the cause of CN or
are simply a secondary manifestation of some other defect.
Effect of phlebotomy and hypertransfusion.
The effect of bleeding and/or hypertransfusion on the
hematological status of grey collies gives interesting
results.78 In the untreated grey collie, EPO levels cycle
out of phase with the reticulocytes and virtually in phase with the
neutrophil counts. After phlebotomy (bleeding of between 10% and 20%
of the blood volume), the cycles in the neutrophils and reticulocytes
continue as they had before the procedure, and there is no change in
the relative phase between the cycles of the two cell types.
Hypertransfusion (with homologous red blood cells) completely
eliminates the reticulocyte cycling (as long as the hematocrit level
remained elevated), but has no discernible effect on the neutrophil
cycle. Most significantly, when the hematocrit level decreases back to
normal levels and the reticulocyte cycle returns, the phase relation
between the neutrophils and the reticulocytes is the same as before the
hypertransfusion. These observations suggest that the source of the
oscillations in CN is relatively insensitive to any feedback regulators
involved in peripheral neutrophil and erythrocyte control, whose levels would be modified with the alteration of the density of circulating cells, and is consistent with a relatively autonomous oscillation in
the HSC (see "Models of the Autoregulatory Control of HSC" below).
Effect of cytokine and lithium therapy.
In both the grey collie72,79 and in humans with
CN,80-82 administration of G-CSF leads to an increase in
the mean value of the peripheral neutrophil counts by a factor of as
much as 10 to 20 and is associated with a clear improvement of the
clinical symptoms. However, G-CSF does not obliterate the cycling in
humans, but rather induces an increase in the amplitude of the
oscillations and a decrease in the period of the oscillations in all
the cell lineages, from 21 to 14 days.80 In human and
canine CN, GM-CSF leads to an increase in neutrophil count by a factor
of between 1.5 and 3.5, which is much less than achieved by G-CSF. In
one report, CM-CSF obliterated cycling.82 Although
recombinant canine stem cell factor (rc-SCF) does not cause
neutrophillia in grey collies, it does obliterate the oscillations of
CN. Lithium therapy in grey collies69,83 has uniformly
yielded an elimination of the severe neutropenic phases and a
diminution in the amplitude of the oscillations without any apparent
change in the period of the oscillation. In humans, there are variable
results with lithium,84,85 and the largest study showed
lack of efficacy and toxicity problems.86
Other Periodic Hematological Disorders Associated With Bone Marrow
Defects
Periodic chronic myelogenous leukemia (CML).
CML is a hematopoietic stem cell disease characterized by
granulocytosis and splenomegaly.87 In 90% of the cases,
the hematopoietic cells contain a translocation between chromosomes 9 and 22 that leads to the shortening of chromosome 22, refered to as the
Philadelphia (Ph) chromosome. The disease is acquired and results from
the malignant transformation of a single pluripotential stem cell, as
shown by the presence of a single G-6PD isoenzyme in the red blood
cells, neutrophils, eosinophils, basophils, monocytes, and platelets in
women with CML who are heterozygotes for isoenzymes A and
B.88 The leukocyte count is greater than 100 × 109/L in 50% of the cases and it increases progressively
in untreated patients. The platelet and reticulocyte counts can also be
mildly elevated. In most cases, the disease eventually develops into acute leukemia.
Morley et al89 was the first to describe oscillations in
the leukocyte count of CML patients in 1967. Several other cases of
cyclic leukocytosis in CML have now been reported.57,90-104 The leukocyte count usually cycles with an amplitude of 30 to 200 × 109 cells/L and with periods ranging from
approximately 30 to 100 days. Oscillations of other blood elements in
association with CML have been observed. The platelets and sometimes
the reticulocytes then oscillate with the same period as the
leukocytes, around normal or elevated numbers. There have been no
specific studies of hematopoiesis in patients with periodic CML. There
is also a report of one patient with periodic acute myelogenous
leukemia.97
Polycythemia vera (PV) and aplastic anemia (AA).
PV is characterized by an increased and uncontrolled proliferation of
all the hematopoietic progenitors and it involves, like CML, the
transformation of a single pluripotential stem cell. Two patients with
PV were reported with cycling of the reticulocyte, platelet, and
neutrophil counts in one case (Fig 2B) and cycling only of the
reticulocyte counts in the other. The period of the oscillations was 27 days in the platelets, 15 days in the neutrophils, and 17 days in the
reticulocytes.55
Finally, clear oscillations in the platelet, reticulocyte, and
neutrophil counts (Fig 2C) were reported in a patient diagnosed as
having AA56 and in a patient with
pancytopenia,105 with periods of 40 and 100 days,
respectively.
Cytokine-induced cycling.
G-CSF is routinely used in a variety of clinical settings, eg, to treat
chronic neutropenia or to accelerate recovery from bone marrow
transplant and/or chemotherapy.58 G-CSF may induce oscillations in the level of circulating neutrophils of neutropenic individuals.42,106-108 When these oscillations arise, they
always seem to be of relatively low period (on the order of 7 to 15 days), and their origin is unclear. There has also been one report of GM-CSF-induced 40-day cycling in a patient with CML after bone marrow
transplant.109
Induction of cycling by chemotherapy or radiation.
Several reports describe induction of a CN-like condition by the
chemotherapeutic agent cyclophosphamide. In mongrel dogs on
cyclophosphamide, the observed period was on the order of 11 to 17 days, depending on the dose of cyclophosphamide.110,111 In
a human undergoing cyclophosphamide treatment, cycling with a period of
5.7 days was reported.112 Gidáli et al113
observed oscillations in the granulocyte count and the reticulocyte
counts with 3 weeks periodicity in mice after mild irradiation. They observed an overshooting regeneration in the reticulocytes and the
thrombocytes but not in the granulocytes. Whereas the CFU-S returned to
normal levels rapidly, the proliferation rate of CFU-S stayed
abnormally elevated.
Five CML patients receiving hydroxyurea showed oscillations in their
neutrophils, monocytes, platelets, and reticulocytes with periods in
the range of 30 to 50 days.95 In one patient, an increase
of the hydroxurea dose led to a cessation of the oscillations. Chikkappa et al114 report a CN-like condition (period
between 15 and 25 days) in a patient with multiple myeloma after 3 years of chemotherapy.
A 89Sr-induced cyclic erythropoiesis has been described
in two congenitally anemic strains of mice,
W/Wv and
S1/S1d.115-117
W/Wv mice suffer from a defect in the HSC,
and in S1/S1d mice the hematopoietic
micro-environment is defective.
The induction of cycling by 89S can be understood as a
response to elevated cell death (see "Models of the Autoregulatory
Control of HSC" below), as can the dynamic effects of chemotherapy.
Periodic Hematological Disorders of Peripheral Origin: Auto-Immune
Hemolytic Anemia (AIHA) and Cyclical Thrombocytopoiesis
Periodic AIHA is a rare form of hemolytic anemia in
humans.118 Periodic AIHA, with a period of 16 to 17 days in
hemoglobin and reticulocyte counts, has been induced in rabbits by
using red blood cell auto-antibodies.119
Cyclic thrombocytopenia, in which platelet counts oscillate from normal
to very low values, has been observed with periods between 20 and 40 days120-136 (reviewed by Cohen and
Cooney126). Although it has been claimed that
oscillations could be detected in the platelet counts of normal
individuals with the same range of periods,137,138 this
conclusion may not be statistically justified.
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HYPOTHESES FOR THE ORIGIN OF PERIODIC HEMATOPOIESIS |
In clinical reports of periodic diseases affecting hematopoiesis,
oscillations have usually been observed only in the blood counts
without examinations of bone marrow precursors and progenitor cells.
However, even in the case of CN in which the kinetics of hematopoiesis
have been extensively studied, the mechanisms responsible for the onset
of periodic oscillations are still unknown. A number of mathematical
models have been put forward that suggest possible mechanisms for the
origin of oscillations in hematopoiesis. These models fall into two
major categories. The first group identifies the origin of the
oscillations with the loss of stability in peripheral control loops
adjusting the production rate of blood precursors to the number of
mature cells in the blood and mediated by TPO, EPO, and G-CSF (Fig 1).
The second group is based on the assumption that oscillations arise in
stem cell populations as a consequence of the loss of stability of
auto-regulatory (local and LR) control loops (Fig 1). A few
investigators have also modeled interactions between these two types of
control loops (see Dunn139 and Fisher140 for
reviews).
Models of the Peripheral Control of Hematopoiesis
It is well known that simple negative feedback systems, such as the
erythroid control system, have a tendency to oscillate. The relative
detail known about erythrocyte production control has not escaped the
attention of modelers who have mathematically explored ways to explain
the results of laboratory manipulations in rodents,141-147
and rabbits119,148 and the nature of the human erythropoietic regulatory system in health and
disease.149-152
The control of erythropoiesis by EPO can be modeled by a single delayed
differential equation describing the rate of change of RBC production
as a function of the death rate of circulating erythrocytes, the rate
of change of cell production after a given perturbation of the
circulating RBC number, and the maturation time of erythrocyte
progenitors. The transition from damped to stable oscillations, which
characterizes the onset of periodic hematopoiesis, depends on the
modification of one or several of these controlling parameters. In
AIHA, the death rate of circulating RBC is increased, whereas the other
parameters lie within normal ranges. The mathematical modeling of the
control of RBC production by EPO indicates that such an increase in the
destruction rate of circulating erythrocytes will induce periodic
fluctuations of erythropoiesis around a low average, with
periods similar to the ones observed in AIHA.153-155 From a
modeling perspective, the laboratory version of rabbit AIHA is thus one
of the best understood periodic hematological diseases.
Similar mathematical treatments have been applied to the control of
granulopoiesis and megakaryopoiesis, even though the existence of
functional peripheral feedback in these systems is still hypothetical.
A few investigators have formulated models for the regulation of
thrombopoiesis138,156-159 assuming the existence of a
negative feedback loop mediated by TPO. Bélair and
Mackey160 specifically considered cyclical
thrombocytopenia. They speculated that elevations in the random
destruction rate of platelets could give rise to the characteristic
patterns observed in cyclical thrombocytopenia. Although modeling
results based on this assumption yielded results qualitatively
consistent with the clinical data, there is still much room for further
study of this problem.
Several models of granulopoiesis incorporate a peripheral negative
feedback loop.161-172 In the grey collie and in CN
patients, the survival of circulating neutrophils is
normal.51 This finding implies that there is not a periodic
elevation of the peripheral death rate of neutrophils in CN, but rather
a periodic modulation of marrow cell production. An alteration of the
peripheral control of granulopoiesis has been proposed as the mechanism
of CN by several investigators.56,110,111,173-185
There is experimental evidence of alterations in the kinetics of
granulopoiesis in CN, ie, the modification of the distribution of
maturation time and the subnormal responsiveness of granulocytic progenitors to CSF. However, recent modeling indicates that these are
insufficient to account for a destabilization of the putative peripheral feedback control of granulocytopoiesis.186
Moreover, the lack of effect of hypertransfusion or phlebotomy on
either cycle (neutrophil or reticulocyte) strongly implies that there is not a direct role of peripheral feedback loops in the origin of the
cycling in CN.
A few attempts have also been made to model periodic CML based on the
peripheral control of granulopoiesis171,187,188 but are
also unsatisfactory in the sense that the models have assumptions on
the kinetic of granulopoiesis in CML that are now known to be
biologically unrealistic.189,190
The occurrence of oscillations in several blood elements in CN and CML
strongly suggests that the oscillations are not a consequence of a
lineage-specific regulatory loop but rather of regulatory mechanisms
affecting all hematopoiesis. The existence of a peripheral feedback
loop controlling granulopoiesis can thus not be supported by the
occurence of oscillations in CN and CML.
Models of the Autoregulatory Control of HSC
Except for AIHA and cyclical thrombocytopenia, the periodic
hematological disorders that have been described are characterized by
the occurence of oscillations in many or all of the peripheral cellular
elements (neutrophils, platelets, lymphocytes, and reticulocytes). Many
have speculated that the origin of these oscillations is in the common
HSC population feeding progeny into the differentiated cell lines.
Mackey191,193 proposed that there could be a loss of
stability in the stem cell population independent of feedback from
peripheral circulating cell types. He analyzed a mathematical model for
a stem cell population in which the proportion of cells entering proliferation depends on the size of the population in G0
(Fig 3). The efflux into the different
commited cell lineages depends on the size of the population, which
varies with the rate of proliferation and the cell death rate.
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| Fig 3.
A schematic representation of the control of HSC
regeneration. Proliferating phase cells include those cells in
G1, S (DNA synthesis), G2, and M (mitosis),
whereas the resting phase cells are in the G0 phase. Local
regulatory influences are exerted via a cell number dependent variation
in the rate of entry into proliferation. Differentiation into all of
the comitted stem cell populations occurs from the G0
population, whereas there is a loss of proliferating phase cells due to
apoptosis. See Mackey191 and Milton and
Mackey192 for further details.
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Other investigators194-202 have considered the dynamics of
auto-regulatory stem cell populations from a modeling perspective applied to various experimental and clinical situations. Ne as et
al40,203-205 have developed such a modeling study based on
experimental evidence that the number of stem cells entering
proliferation is controlled by the number of DNA-synthesizing cells.
Cell to cell interactions or cytokines that are essential for the
growth of HSC in vitro, such as IL-3 and SCF, could be involved in the autoregulation of HSC proliferation.
Because of the delay in the autoregulation loop, due to the time
necessary for replicating cells to go through the S phase and the
mitotic phase, this system has a tendency to oscillate. In normal
conditions it is assumed that the population does not oscillate.
Mackey191 showed that an abnormally large irreversible cell
loss within the proliferating compartment, which can represent either
apoptosis or other cell death, would induce oscillations of the number
of stem cells. Figure 4 shows the
variations in the amplitude and the period of the oscillations
predicted by the model as the apoptotic rate is increased. An increase
in the apoptotic rate of HSC also induces a decrease in the average
efflux from the HSC to all the cell lineages. This is consistent with the occurence of oscillations in all the blood elements in some patients with AA, in which all the blood cell counts are low, as well
as the oscillations observed in several cell lineages after
chemotherapy or radiation. The range of periods obtained by Mackey
depends largely on the rate of irreversible cell loss and on the cell
cycle time delay. Depending on the value of these parameters, the
period can vary from 16 to 43 days in humans and from 9 to 26 days in
dogs. In most periodic hematological disorders, large differences
consistent with these values have been observed in the period of the
oscillations between different individuals.
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| Fig 4.
(A) Schematic representation of the effects of increasing
apoptotic rate on the HSC dynamics, as predicted from the model
proposed previously.191,192 The diagram shows the effect of
administering the same dose of 89Sr to
W/Wv and S1/S1d mice on
the amplitude and the period of the oscillations. The dashed lines show
the onset and the end of oscillations as the apoptotic rate increases.
(B) Computer simulations of the normalized HSC efflux
predicted191 for increasing apoptotic rates (from I to V).
As the apoptotic rate is increased, the period of the oscillations
increases and the amplitude increases and decreases consecutively.
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The model also gives a plausible explanation for the 89Sr
induction of cyclic erythropoiesis in the two congenitally anemic strains of mice, W/Wv and
S1/S1d (Fig 4). Assume that the difference
between W/Wv and S1/S1d
mice is solely related to differences in the rate of
apoptosis.206. (The observation that
S1/S1d mice are more refractory to
erythropoietin than W/Wv mice suggests that the
apoptotic rate is higher in S1/S1d.) The results
of Mackey191 predict that a higher rate of apoptosis would
increase the likelihood that an oscillation in erythrocyte number
occurs. Indeed, in contrast to W/Wv mice,
approximately 40% of S1/S1d mice have
spontaneous oscillations in their hematocrit.115,116 In
both strains of mice, a single dose of 89Sr is sufficient
to increase apoptosis into a range associated with oscillations in
erythrocyte number. Because the apoptotic rate for the
S1/S1d mice is greater than that for
W/Wv mice before 89Sr, it is
reasonable to expect that it will also be higher after administration
of equal doses of 89Sr to both strains of mice. As
predicted, the period of the oscillation is longer, the amplitude is
larger, and the mean hematocrit is lower for
S1/S1d mice than they are for
W/Wv mice.192
The Particular Cases of CN and CML
Destabilization of an early HSC population resulting in oscillations
with a large range of periods in all the blood elements after radiation
or chemotherapy and in AA may also be at the origin of the oscillations
observed in CN and CML. Modification of any of the parameters in the
model described in Mackey191 (Fig 3) can potentially induce
the onset of oscillations.
Even though all the blood elements are often oscillating in periodic
CML and CN, the defect in these two disorders primarily affects
granulopoiesis. The abnormal responsiveness of CFU-G explains the low
ANC levels in CN, which may induce an alteration in the cytokine
levels. The fact that G-CSF is the only cytokine shown to alter the
period of the oscillations in all the blood elements shows that it
plays a crucial role in the mechanism at the origin of the oscillations
in CN. The finding that G-CSF not only regulates granulopoiesis, but
also affects the kinetics of early HSC suggests that its effect on the
oscillations in CN may be mediated through the modification of HSC
dynamics. In vitro studies of the effect of G-CSF suggest that it
increases the rate of entry into cycling, which is likely to
destabilize the steady state while increasing the average size of the
population. This is consistent with the mildly elevated platelet,
monocyte, and lymphocyte counts often observed in CN. Similar
mechanisms may also induce the oscillations in CML.
The mechanisms underlying the complex dynamical features of CN and
periodic CML will more likely be understood with the use of models that
include both the local autoregulation of early stem cells and its
relation with the more mature hemopoietic compartments. The multilevel
effect of cytokines such as G-CSF suggests indeed that strong
relationships exist between the regulation of early and late
hematopoietic compartments.
| |
CONCLUSION |
This review focuses on the clinical and laboratory findings in periodic
hematopoietic diseases, including CN, periodic CML, AA, PV, AIHA, and
cyclical thrombocytopenia. With the exception of the latter two, the
available evidence indicates a broad involvement of the entire
hematopoietic system, because cycling is typically observed in more
than one of the mature hematopoietic cell types.
Cycling in one or several hematopoietic cell lineages is probably much
more frequent than reported and would be detected if serial blood
counts were systematically performed. These observations suggest a
major derangement of the dynamics of one or more of the stem cell
populations such that they become unstable and generate sustained
oscillations that are manifested in more than one of their progenitor
lines. Mathematical modeling studies suggest that there are several
ways in which the HSC dynamics can be destabilized and give rise to
oscillations if they are controlled by an autoregulatory loop. The
finding that lineage-specific cytokines also have an effect on early
HSC regulation implies that oscillations could arise as a result of the
alteration of only one compartment, such as observed in CN and CML.
Analysis of the effect of the cytokines on the dynamical features of
these disorders, through modeling studies, may be a key to the
understanding of the nature of early hematopoiesis regulation.
| |
FOOTNOTES |
Submitted December 8, 1997;
accepted June 25, 1998.
Supported by the Natural Sciences and Engineering Research Council
(NSERC Grant No. OGP-0036920, Canada), the National Institutes of
Health (NIH Grant No. 18951, USA), Le Fonds pour la Formation de
Chercheurs et l'Aide à la Recherche (FCAR Grant No. 98ER1057, Québec), and the École Normale Supérieure de
Paris.
Address reprint requests to Michael C. Mackey, PhD,
Departments of Physiology, Physics, and Mathematics, Center for
Nonlinear Dynamics in Physiology and Medicine, McGill University,
McIntyre Drummond Building, 3655 Drummond St, Montreal H3G 1Y6, Quebec, Canada.
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Abstract
Article
Abstract