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Clinical Features and Studies of Erythropoiesis in Israeli Bedouins With
Congenital Dyserythropoietic Anemia Type I
By Hannah Tamary, Hanna Shalev, Drorit Luria, Dina Shaft, Meira Zoldan, Lea Shalmon, Ana Gruinspan,
Batya Stark, Marta Chaison, Eilat Shinar, Peretz Resnitzky, and Rina Zaizov
Congenital dyserythropoietic anemia (CDA) type I is a rare
macrocytic anemia of unknown etiology. In the present
study, we redefined the clinical and laboratory picture of
CDA type 1, some of its pathogenic aspects, and the association with thalassemia-like features in 20 patients, all of
whom belong to one Bedouin tribal group and are probably
descended from a common ancestor. In each case ultrastructural studies of bone marrow (BM) erythroblasts showed
the classic morphologicalfindings of CDA type 1. Serological
tests for CDA type II were negative. The clinical picture was
variable, but mostly benign. Some patients displayed elevated hemoglobin A2 levels or a high ratio of a-to non-a
globin. However, neither family studies nor complete sequence analysis of the p-globin was compatible with pthalassemia. Increased erythropoiesis was manifested by a
high number of BM erythroid burst-forming units. Serum
erythropoietin was also elevated. BM flow cytometry studies demonstrated arrest of erythroid precursors in the S
phase of the cell cycle. The ultrastructural morphological
features of the erythroid precursors, showing peripheral
chromatin condensation, suggest apoptosis. AddiCional
studies are indicated to define the molecular basis of this
disease.
0 1996 by The American Society of Hematology.
C
CDA type I in this homogeneous population in an attempt
to clarify the pathogenesis of the disorder and its association
with thalassemia.
ONGENITAL dyserythropoietic anemias (CDAs) are a
rare group of red blood cell (RBC) disorders of unknown etiology characterized by ineffective erythropoiesis,
pathognomonic cytopathology of the nucleated RBCs in the
bone marrow (BM) and secondary hemochromatosis. In
1968, Heimpel and Wendtl classified these disorders into
three types, which were later confirmed by electron microscopy and serological findings.' Type I is characterized by
congenital macrocytic anemia, megaloblastoid erythroid hyperplasia, and the presence of nuclear chromatin bridges
between erythroblasts. More than 60 sporadic cases of CDA
type I have been reported in the literat~re.~"
The typical
morphological ultrastructural studies accompanied by negative acidified serum lysis and adult i/l agglutination test constitute the major diagnostic features. The more common type
11, also known as hereditary erythroblastic multinuclearity
with a positive acidified serum test (HEMPAS): is characterized by normocytosis or macrocytosis with binucleated and
multinucleated marrow erythroblasts and karyorrhexis. Type
111is manifested by macrocytosis and erythroblastic multinuclearity with prominent gigantoblask3
More than 30 documented cases could not be clearly assigned to type I, 11, or III.3 Type IV was the classification
used in four reports in which BM morphology resembling
that in type I1 was accompanied by negative acid serum
tests5 CDA in association with thalassemia has been described in 17 patients.'.' Members of more than a dozen
other families had CDAs that were even more difficult to
cla~sify.~
Anselstetter et a19in 1977 were the first to report that band
3 glycoproteins from HEMPAS erythrocyte membranes migrate faster than those obtained from normal erythrocyte
membranes. Reduced levels of N-glycans in HEMPAS
erythrocyte membranes with low N-acetylglucosaminyltransferase I1 activity have been documented in some patients," and a defect in the a-mannosidase I1 gene was reported in one patient." Faulty glycosylation of transfemn,
a glycoprotein produced in the liver, has also been described.I2The molecular basis for the defects in other CDAs
is not known.
In the following study, we describe 20 patients with CDA
type I who belong to seven Bedouin families living in the
Negev (the southern part of Israel). The aim of the study
was to redefine the clinical and laboratory characteristics of
Blood, Vol 87, No 5 (March 1). 1996: pp 1763-1770
MATERIALS AND METHODS
Twenty patients (14men, 6 women), aged 1 to 23 years (median,
10 years) from seven families were evaluated. Three patients were
originally diagnosed and followed at our center, and the medical
records of the 11 patients followed for anemia at the Soroka Medical
Center in Beersheva were reviewed. Six additional patients were
identified in the course of family studies. Each of the 20 patients
underwent a complete physical examination. Bone age was determined in six patients. Control BM samples for culture studies and
flow cytometry studies were obtained from healthy children who
were donors for BM transplant. &thalassemia major BM samples
were obtained at diagnosis. The following blood and BM examinations were performed for each patient.
Routine blood tests. After obtaining informed consent, venous
blood was drawn. A complete blood count was performed using an
HI counter (Technicon, Israel). Measurement of serum folic acid
and vitamin Bl2 levels, hemoglobin electrophoresis, determination
of anti-I and i antigen titers, and Ham and Coombs tests were all
performed using standard technique^.'^ Ferritin levels were measured
by a sandwich enzyme immunoassay (Melisa Kit, Cambridge Life
Science, Cambridgeshire, England). Serum erythropoietin (EPO)
levels were determined using a diagnostic kit with microtiter wells
~
From the Pediatric Hematology-Oncology Center, Schneider's
Children's Medical Center of Israel, Petah Tiqva; Pediatric Hematology-Oncology Research Laboratory, the Felsenstein Medical Research Center, Beilinson Medical Campus, Petah Tiqva; Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv: Division of Pediatrics, Soroka Medical Center, Beersheva; Internal Medicine B and
the Efrati Research Institute for Blood Cells and Cytology, Kaplan
Hospital, Rehovot; and Magen David Adom National Blood Services
Center, Tel Aviv, Israel.
Submitted January 30, 1995; accepted October IO, 1995.
Address reprint requests to Hannah Tamary, MO, Pediatric Hematology-Oncology, Schneider 's Children's Medical Center of Israel, 14 Kaplan St, Beilinson Medical Campus, Petah Tiqva 49 202,
Israel.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 19% by The American Society of Hematology.
0006-4971/96/8705-0030$3.00/0
1763
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1764
coated with antierythropoietin-specific IgG (JCL Clinical Research
Corporation, Knoxville, TN).
BM elecrron microscopic studies. For ultrastructural evaluation,
aspirated BM cells were fixed overnight at 4°C in Karnovsky's fixative'" in 0.1 mol/L cacodylate buffer and postfixed in 1% osmium
tetroxide for 1 hour. After washing in cacodylate buffer, the specimens were subjected to dehydration by passage through a graded
series of ethanol concentrations andpropylene oxide andfinally
embedded in epon 812. Thin sections were then collected on copper
TAMARY ET AL
grids. counterstained with uranyl acetate and lead citrate, and examined under a Philips 201 electron microscope. Peripheral erythroid
colonies were treatedas above and observed under an electron microscope.
BM and peripherctl blood culture studies. BM andperipheral
blood were obtained forassays of erythroid colony formation. Heparinized BM or peripheral blood were layered over a discontinuous
Histopaque-l077 gradient (Sigma Diagnostics, St Louis, MO) and
centrifuged (204s. 4°C) for 25 minutes to remove neutrophils and
Fig 1. Electron microscopy oferythroid precursors in BM. (A) Four normoblastswith typical CDA type 1features: sponge-like heterochromatin; enlargement of nuclear pores; invagination of cytoplasm into nuclear area (magnification x 4,766). (B)Left lower normoblast of (AI:
spongy heterochromatin structure (a); enlarged nuclear pore (b); invagination of cytoplasm into nucleus; iron-loaded mitochondria (arrow)
type
CDA I normoblast
[magnification x 24,126). (C)Typical binucleatedCDA type I normoblast with nuclear bridge (magnification x 8,896).(D)
showing prominent apoptotic features: peripheral nuclear condensationof hetrochromatin (arrows), disruption of nuclear pores (arrowhead)
and conservation of cytoplasmic organelles. Mt. mitochondria,(magnification x 21,7601.
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1765
ERYTHROPOIESIS IN CDA TYPE I
Family
2
1
3
1
Family
7
Fig 2. Pedigree of families
with CDA type 1. Blocked symbols represent subjectcr diagnosed as CDA type I; hatched
symbols represent subjects with
CDA type I but not available for
study.
T
RBC membrane skeletal proteins. RBC membranes were prepared by hypotonic lysis of the cells in 5 mmol/L sodium phosphate,
pH 8,*”supplemented with 1 mmol/L ethylenediamine tetraacetic
acid (EDTA) and protease inhibitors. Polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate was performed using
the continuous method described by Fairbanks et a1,2” as modified
by Steck,” and by the discontinuous method of Laemmli.”
DNA Jow cytomerry. Marrow mononuclear cells were separated
by density gradient centrifugation on Histopaque 1077 (Sigma Diagnostics).*’ ‘‘Pure’’ erythroid populations were separated by panning
and selecting cells negative for CD45, a membrane protein present
on cells of lymphoid and myeloid lineages, with magnetic beads.
Table 1. CDA Type I-j?-Thalassemia-LikeFeatures
Case
No.
F1-l
F1-2
F1-3
F2-1
F2-3
F3-1
F3-2
F3-3
RBCs. The buoyant mononuclear cells obtained from the gradient
F4-1
interface were washed twice in Iscove’s modified Dulbecco medium.
F4-2
Erythroid colony assays were performed as previously de~cribed.’~
F4-3
Sensitivity to erythropoietin was determined by using increasing
F4-4
concentrations of EPO ( I to 8 UlmL). For assay of peripheral coloF7-1
nies, the cultures were supplemented with EPO (2 UlmL) and inF7-2
terleukin-3 ( I O UlmL).
Mean
Cytogenetic studies. Chromosome analysis was performed on
2 SD
BM samples directly and after 24 hours culture’6 and on peripheral
Normal
blood lymphocytes stimulated for 2 hours with phytohemagglutiMean
nin.” A trypsin-Giemsa technique was used for chromosomal bandt- SD
ing.” Chromosomes were described according to the International
System for Human Cytogenetic Nomenclature.’’
WLI
Hb
MCV
(fL)
HbAZ
%
73
79
89
84
93
85
94
90
91
80
87
81
84
82
85
6
93
106
105
97
104
98
95
105
94
101
107
102
97
92
98
5
3.9
2.9
5.1
3.8
3.4
3.3
3.4
3.1
3.4
3.5
3.4
3.3
3.0
3.8
3.5
0.5
120
6
81
6
2.5
1
Abbreviation: N, normal sequence.
HbF
%
1.1
5.0
1.1
1.6
5.8
0.5
1.1
0.5
0.5
1.4
0.5
1.2
6.0
1.6
2.0
1.9
<1
ai4
+Y
1.28
1.38
1.39
1.15
1.25
1.00
0.97
1.72
1.13
1.40
1.42
1.10
1.21
1.25
1.27
0.18
1.06
0.19
,%Globin Gene
Seauence
N
N
N
N
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1766
TAMARY ET AL
B
A
300
300
250
250
Y
d
T
v)
j200
,o 200
z
W
0
X
Y)
sx 150
cu
z
(Y
\
8
4 100
9
8
150
I?
8 100
50
50
0
T
T
I
0
1
2 3 4 5 6 7 8
ERYTHROPOIETIN U I ml
9
10
0
1
2 3 4 5 6 7 8
ERnHROPOlETlN U I ml
9
10
Fig 3. Marrow erythroid colonies dose-response curves to €PO. The number of CFU-E and BFU-E derived colonies/2 x IO5 cells in response
to EPO, 1 to 8 U/mL is depicted. Each point represents the mean result of six different experiments, the bars expressing the standard error
of the mean ISEM). (A) control marrow; (B) CDA type I marrow showing increased numbers of BFU-E and CFU-E as compared with normal
marrow.
Samples of whole marrow mononuclear cells and CD45-negative
and -positive cells were stained with propidium iodide (PI) to determine DNA content.” The fluorescence of the PI-stained cells was
measured, as previously described, with a FACS-star analyzer (Becton Dickinson, Immunofluorocytometry System, Mountain View,
CA).” Cell cycle distribution was calculated according to the “Cell
FIT” computer program (version 2.1) (Becton Dickinson, San Jose,
CA). Bromodeoxyuridine (BrdU) staining was performed as previously described.” In brief, BM cells were pulse-labeled for 30
minutes with 10 pmoUL BrdU, washed twice with phosphate-buffered saline (PBS) containing 1% bovine serum albumin, fixed in
70% cold ethanol for 30 minutes on ice, and rehydrated ovemight
in PBS at 4°C. Staining with anti-BrdU antibodies conjugated to
fluorescein isothiocyanate (Becton Dickinson) was performed after
acid denaturation (incubation with 2N HC1-0.5% Triton X-100 for
30 minutes) and neutralization with NaZB407(pH 8.5). The cells
were subjected to RNase A before analysis. For double staining, 1
pg PVmL was used.
Globin chain synthesis. The globin synthesis ratio of peripheral
blood reticulocytes was calculated after separation of globin chains
labeled with ’H-leucine on a carboxymethyl cellulose column.”
P-Globin gene amplijcation and sequencing. Genomic DNA
was isolated from white blood cells,zx and the 0-globin gene was
amplified in two fragments by the polymerase chain reaction.*’ The
biotin-avidin system and magnetic beads were used to produce highquality single-stranded template DNA, which was then sequenced
directly by the dideoxy chain termination method.Z9.’o
RESULTS
Diagnosis of CDA type I. Diagnosis of CDA type I was
based on the presence of macrocytic anemia and typical BM
findings under light microscopy, including large erythroblasts with incomplete nuclear division and a chromatin
bridge connecting the nuclei of two cells. Diagnosis was
confirmed in all patients on the basis of typical BM electron
microscopy characteristics, including spongy heterochromatin, enlargement of nuclear pores, invagination of the cytoplasm into the nuclear area, and iron-loaded mitochondria
(Fig 1). Serological tests for CDA type I1 were all negative.
Clinical datu. Fourteen of the 20 patients studied were
the products of consanguineous marriages (Fig 2). In six
families, there was more than one affected child. All families, although thought to be unrelated, belong to the same
tribal group. Fourteen patients presented with anemia, while
six were detected in the course of family studies. The age
at diagnosis varied from birth to 23 years. Eight patients
were diagnosed during the neonatal period, while an additional three were diagnosed between the age of 1 and 12
months.
Six patients required occasional blood transfusions. Two
patients presenting at the neonatal period were more severely
affected. One patient required monthly RBC transfusions
until he underwent splenectomy at the age of 4 years and
became transfusion-independent with Hb levels of 8 to 9.5
gr%. The other patient required RBC transfusions twice a
year, however, because of increasing splenomegaly and
transfusion requirement, splenectomy was performed at the
age of 5 ‘I2 and since then she has maintained a hemoglobin
level of 8.5 to 10.5 gr% with no need for transfusion.
Growth parameters and physical examination. The
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ERYTHROPOIESIS IN CDA
m 'm-
1767
c - ~ . ~ ( B A
._.
'
Fig 4. Electronmicroscopy of peripheralBFU-E. (A) Part of normal
peripheral blood BFU-E colony at day 10 (magnification x 1,874). (B)
Part of peripheral blood BFU-E colony from patient with CDA type 1,
displaying typical dyserythropoietic features (magnification x 5,504).
IC)Erythroblast from above BFU-E colony showing spongy appearance of heterochromatin(a); enlarged nuclear pores (b);invagination
of cytoplasm into nucleus (arrow);iron-loadedmitochondria (arrowheads) (magnification x 15,2001.
height standard deviation score (SDS) was calculated and
expressed as the number of standard deviations from the
mean of each patient's height, as described by Tanner et al."
The mean height SDS was - I .55 t 1.02 with only four
patients more than 2 SD below the mean height for their
age. All patients presented with mild icterus, 1 I had mild
splenomegaly, and IO had mild hepatomegaly.
hhorcztory dlrrcz. Hemoglobin levels ranged from 72 to
104 g/L (mean, 86 5 8 g/L); mean corpuscular volume
(MCV) was high, ranging from 90 to 107 fL (mean. 101 5
5.3 fL).Absolute reticulocyte counts ranged between 18 to
112 X IO"/L (mean, 51 t 22 X IO1%). lndirect bilirubin,
as well as serum lactate dehydrogenase, were elevated, haptoglobin was low, and ferritin was moderately elevated, ranging from 48 to 1245 &L (mean, 385 t 293 pg/L; normal
value, 10 to 300 pg/L). The results of the acidified serum
test were negative and Vi titers were within the low adult
range. Folic acid and B12levels were normal. Serum EPO
levels were mildly elevated: 18 to 1 12 miu/mL (mean, 53 5
27 miu/mL; normal range, 22 to 54 miu/mL). Chromosomal
studies of four patients showed a normal peripheral blood
and BM karyotype. RBC membrane studies did not show
any abnormality in the polypeptide membrane pattern or the
abnormal, fast moving band 3 previously reported in CDA
type 11." No globin excess was present. The percentage of
hemoglobin (Hb) A2 was abnormally high (range, 3.8% to
5.1%) in four of the 14 patients examined. The parents of
the patients in family 1 (Fig 2) had normal counts and Hb
A2 and Hb F levels. In nine of the 14 patients, globin synthetic ratios were abnormal (1.25 to 1.72). within the pthalassemia minor range (Table I).
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1768
TAMARY ET AL
p, , , , pp, , , ppp,
-B
? E l1
?O
-m
, 11%
-
I
, ppp, , 1
SO
Gt- 1217
S- 4 6 1
G2+M- 1.9%
U"U " :
.-
I ? :
d
*
-
C
c
a
.-
a
9 -
e4
so P
sen
-
--
a
U
U
a
1
0
0
L
I?
.
aI
*a
C
C
i
9
FLP-U
BM and peripheral blood culture tests. A 3 14% ? 141 %
increase in marrow colony forming unit-erythroid (CFU-E)
was found upon the addition of erythropoietin (2 U/mL),
with burst forming unit-erythroid (BFU-E) rising only to
164% ? 46%, and colony forming unit-culture (CFU-C)
growth 162% 2 61% that of the control. There was a mild
increase in CFU-E and BFU-E, with increasing erythropoietin concentrations (Fig 3). Serum supplementation was not
associated with greater numbers of erythroid colonies. The
number of BFU-E in peripheral blood cultures was 140% 2
Fig 6. Cells were doublastained with PI and anti-BrdU-Ab conjugated t o fluorescein isothiocyanate (FITC) and analyzed by FACS. (A)
Normal proliferating K562 cell line showing 43% of cells in active S
phase (AS), 46% in G1,6% in G2/M, and 3% in arrested S phase (FS).
(BI CDA type Iwhole marrow cells showing no cells in active S phase
and 11% arrested in S phase. (C) CDA type IC M 5 + cells, the majority
in Gl/Go. ID) CDA type I CD45- cells, with 35% arrested in S phase.
Fig 5. f l o w cytometry cell cycle distribution and DNA content. X-axis, relative DNA content; Y-axis, cell number. (A)
Normal marrow and p-thalassemia major marrow showing
diploid DNA content. (B) CDA
type I bone marrow cells arrested at S phase. (C) CDA type
1, CD45+ population (nonerythroid), showing normal DNA
content. (D) CDA type I CD45(erythroid) marrow cells, mainly
in S phase.
86% that of the control. Ultrastructural BFU-E studies
showed abnormal erythroid cell morphology, with a spongy
appearance of the condensed chromatin and enlargement of
nuclear membrane pores (Fig 4).
BM DNA jlow cytometry studies. Normal and B-thalassemia major BM had normal DNA content, with most cells
in the Go/Gl phase. However, in four of the patients with
CDA type I, 47.6% z? 2.7% of the BM cells were in the S
phase, versus 2.9% 2 1.7% of normal marrow cells (Fig 5).
On separation of the erythroid cells, the pathological findings
proved to be confined to the erythroid precursors, whereas
the myeloid and lymphoid cells (CD45 +) had a normal
DNA content. Whole and separated BM cells were doubly
stained with PI and fluorescent anti-BrdU (Fig 6). Doubleparameter (BrdU plus PI) analysis distinguishes between
cells engaged in active DNA synthesis and those arrested in
the S phase. As can be seen in Fig 6, 35% of the CD45mononuclear (erythroid) cells were arrested in the S phase.
Globin synthesis and globin gene sequence. Although
four of the 14 patients examined displayed normal A2 values
and six of the 14 displayed aberrant globin synthetic ratios
(Table I), base changes causing &thalassemia were not evident on sequencing of the &globin gene in four such patients. Furthermore, the parents of three CDA type I siblings
with increased levels of hemoglobin A2 and abnormal globin
synthetic ratios had normal hemoglobin, MCV and hemoglobin A2 values, and normal globin synthetic ratios (Fig 2,
family I), thus excluding any association with &thalassemia.
DISCUSSION
About 60 cases of CDA type I have been reported in the
literature, most of them sporadic..' We studied 20 Israeli
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ERYTHROPOIESIS IN CDA TYPE I
Bedouins with CDA type I (Fig 2). The Bedouins living in
Israel originated in the Arab Peninsula and belong to three
main tribal groups confederation^).^' Although all our patients are members of what seem to be unrelated families,
they all belong to the same tribal group and probably stem
from a common ancestor. The observed familial pattern
clearly favors recessive autosomal inheritance as previously
suggested.'
Increased erythropoiesis was manifested in our CDA type
I patients by the large numbers of BM and peripheral blood
erythroid colonies displaying the characteristic findings of
condensed nuclear chromatin and abnormal nuclear membrane pores (Fig 3). The high number of peripheral blood
and marrow CFU-E colonies, as well as their abnormal morphology, may suggest involvement of the committed stem
cells and could serve as an additional diagnostic tool in CDA
type I.
Variant globin chain synthesis has been described in 17
CDA patients from nine different fa mi lie^.^.',^^,^^ Although
some of these patients may represent authentic cases of thalassemia with coexistent CDA, none was documented definitively. Our &globin sequence data on four patients, augmented by family studies (Fig 2), suggest that in our CDA
type I patients, P-thalassemia can be excluded and that the
imbalance in globin chain synthesis is probably secondary
to the basic erythropoietic defect.
Several pathogenic mechanisms have been implicated in
CDA type I.3 The plasma membrane has been considered a
possible site of the primary lesion, with nuclear membrane
breakdown secondary to the abnormal plasma membrane.
We did not find any abnormal band on RBC membrane
protein electrophoresis. Theoretically, nuclear membrane defects and a sponge-like nucleus could also be caused by
abnormal histones. Indeed, abnormal histone content has
been reported in CDA type I erythroblast^.^^ Heimpel and
Wendt,' and later Wickramasinghe and P i ~ p a r d ,using
~~
Feulgen microspectrophotometry and [3H]-thymidineautoradiography, demonstrated gross abnormalities of proliferation
in early polychromatophilic erythroblasts. The aberrations
included arrest of DNA synthesis after cell progression
through part of the S phase and formation of mononucleate
and binucleate cells with hypertetraploid DNA content.
Based on earlier findings, we performed DNA flow cytometry studies on BM from four CDA type I patients (Fig 5).
An increased number of erythroid cells in the S phase of
mitosis were found in all of them. DNA content and cell
cycle distribution were normal in BM CD45 + (nonerythroid) cells (Fig 5C) and in normal and P-thalassemia major
whole BM (Fig 5A). Flow cytometry studies and cell cycle
analysis, using double labeling with PI and BrdU (Fig 6),
showed the arrest of CDA type I marrow erythroid cells in
the S phase.
Apoptosis, programmed cell death, involves in series of
morphological change^.^' Nuclear changes in early stages
of apoptosis begin subjacent to the nuclear membrane. The
chromatin assumes a characteristic pattern, extending as a
band beneath the inner lamina of the nuclear membrane.
The peripheral condensation of chromatin in CDA type I
erythroblasts resembles the initial changes observed in cells
undergoing apoptosis (Fig ID). However, we failed to dem-
1769
onstrate DNA ladders in CDA type I BM. It was previously
suggested that morphological features of apoptosis may occur in the absence of interchromosomal DNA fragmentation,
which could be a later event in the apoptotic pro~ess.~'
Recently, S-phase arrest and apoptosis were described in
overexpression of p34'"'
at an inappropriate phase in the
cell cycle.39p34'"'
is a serine threonine kinase, one of the
newly reported cyclin-dependent kinases (cdks) that drive
the cell ~ y c l e . ~When
"
p34'"'
complexes with cyclins A
and B, it controls cell entry into mitosis. Premature activation
of ~34'~'' promotes dissolution of the nuclear membrane
and chromatin condensation. This may be a general mechanism by which cells undergoing apoptosis initiate disruption
of the nucleus, as proposed by Shi et al.39Further studies
are indicated to better characterize the role of erythroid S
phase arrest and apoptosis and their relation to the basic
defect in CDA type I.
ACKNOWLEDGMENT
We are indebted to Professor Elias Schwartz, of the Children's
Hospital of Philadelphia for his careful review of the manuscript
and to Dr Alexandra Mahler for her skillful assistance in preparation
of the manuscript.
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2. Lewis SM, Frisch B: Congenital dyserythropoietic anemias:
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7. Hurby MA, Mason RG, Hoing GR: Unbalanced globin chain
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8. Eldor A, Matzner Y, Kahdne I, Levene C, Polliak A: Aberrant
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1996 87: 1763-1770
Clinical features and studies of erythropoiesis in Israeli Bedouins with
congenital dyserythropoietic anemia type I
H Tamary, H Shalev, D Luria, D Shaft, M Zoldan, L Shalmon, A Gruinspan, B Stark, M Chaison, E
Shinar, P Resnitzky and R Zaizov
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