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HEMATOPOIESIS
From the Division of Hematology/Oncology, Department of
Medicine, Cedars-Sinai Medical Center, Burns and Allen Research
Institute, University of California, Los Angeles, School of Medicine;
the Department of Hematology, Showa University School of Medicine,
Tokyo, Japan; the Division of Hematology/Immunology, Kanazawa Medical
University, Uchinada, Japan; and the Laboratory of Chemical Biology,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD.
Iron is essential for cell proliferation, heme synthesis, and a
variety of cellular metabolic processes. In most cells, transferrin receptor-mediated endocytosis is a major pathway for cellular iron
uptake. Recently, transferrin receptor 2 (TfR2), another receptor for transferrin, was cloned. High levels of expression of TfR2 messenger RNA (mRNA) occur in the liver, as well as
in HepG2 (a hepatoma cell line) and K562 (an erythroid leukemia cell line). In this study, TfR2 mRNA expression was analyzed in
hematological cell lines, normal erythroid cells at various stages of
differentiation, and leukemia and preleukemia cells. High levels of
TfR2 expression occurred in all of the erythroid cell lines
that were examined. Erythroid-specific expression of TfR2 protein
in bone marrow cells was confirmed by immunohistochemical staining.
Expression of TfR2 mRNA was high in normal
CD34+ erythroid precursor cells, and levels
decreased during erythroid differentiation in vitro. Levels of
expression of TfR2- Iron is essential for a variety of physiological
activities of cells, such as electron transport and DNA synthesis, and
it is used as a cofactor of cytochromes, aconitases, ribonucleotide reductase, and heme proteins.1,2 Transferrin receptor 1 (TfR1) is a type II membrane protein that mediates cellular iron
uptake. In the serum, most iron exists in a transferrin-bound
form.3 On the cell surface, iron-bound transferrin binds
to TfR1; this is followed by internalization of this complex.
Recently, another receptor for transferrin, transferrin receptor 2 (TfR2), was cloned in our laboratory.4 At least
2 alternatively spliced forms of transcripts, Considering our limited knowledge of the expression profile of
TfR2, we asked the following questions: (1) Is
TfR2 expression, as a previous report6
suggested, specific to erythroid cells within the hematopoietic
population? (2) Iron is essential for cell growth, and we previously
showed that expression of TfR2- Cell lines
Immunohistochemistry
Preparation of human erythroid cells at various stages of differentiation Human erythroid cells from buffy coats were cultured as previously described.16 Briefly, the mononuclear cells were obtained by density centrifugation in lymphocyte separation media (Organon Teknika, Durham, NC). The cells were cultured in the Phase I -Eagle minimum essential medium (-MEM) (Sigma, St Louis, MO)
containing 10% fetal bovine serum (FBS) (Intergen, Purchase, NY), 10%
conditioned media prepared from supernatant of 5637 carcinoma bladder
cells, and 1 µg/mL cyclosporin A (Sigma). After 7 days' incubation,
the cells were washed with phosphate-buffered saline and
transferred to Phase II -MEM media containing 30% FBS; 10% bovine
serum albumin; 10 5 M 2-mercaptoethanol; 106
M dexamethasone; 0.033 g/L (33 µg/mL) holotransferrin; 10 ng/mL stem cell factor (Sigma); and 1000 U/L (1 U/mL)
erythropoietin (Amgen, Thousand Oaks, CA). After 4 days in Phase II
culture, the cells were collected and incubated for 30 minutes with a
cocktail of antibodies against the following cell surface markers: CD2, CD19, CD33, and CD66b. After incubation for an additional 30 minutes with Stemsep Magnetic colloid, the cells of interest were isolated by
negative selection with a 0.6 Tesla magnet (StemCell Technologies, Vancouver, BC, Canada). Stage-specific cell populations
(CD34+/d4, and glycophorin A [GPA]/d4) have been
isolated from the erythroid population by positive selection with
anti-CD34 and anti-GPA antibodies (Stem Cell Technologies),
respectively. To obtain erythroid cells from a later stage of
maturation, both cell depletion and positive selection by means of GPA
have been applied to erythroid cultures that have been incubated for 10 days in Phase II (GPA/d10). Alternatively, the CD34+/d4
progenitors were cultured in the same media for up to 14 days. The
purity and homogeneity of these populations were confirmed by
flow-cytometry analysis.
Quantitative RT-PCR for human erythroid cells at various stages of differentiation The mRNA was extracted from human erythroid cells prepared as above, and complementary DNA (cDNA) was synthesized. Real-time quantitative PCR (Q-PCR) was performed with primers specific for TfR1 (5'-AAA ATCCGGTGTAGGCACAG-3' and 5'-CCTTTAAATGCAGGGACG AA-3'); TfR2 (5'-TACCCATTCCTGCACACA AA-3' and 5'-AGTACACCCACTGCAGGG TC-3'); and TfR2- (5'-ACCTGGAGGAGGAAGAGGAA-3' and 5'-CGACGTAGCCCAGTAGGAAG-3'). Primer specificity was confirmed by restriction endonuclease and agarose gel analysis. Sybr green I dye (Molecular Probes, Eugene, OR)
was used as the reporter dye for Q-PCR, which was performed in a PE
Biosystems SDS 7700 thermal cycler (PerkinElmer, Boston, MA).
Results are presented as attomoles per microgram mRNA.
RT-PCR for clinical samples From a collection at Showa University School of Medicine (Tokyo, Japan), 107 leukemia and preleukemia samples from 90 patients were analyzed for TfR1, TfR2-, and TfR2-
expression by semiquantitative RT-PCR. Either BM or peripheral blood
mononuclear cells (PBMNCs) were used. These samples were from patients
with AML (38 BMs and 25 PBMNCs); CML (chronic or accelerated phase, 5 BMs and 4 PBMNCs); acute lymphocytic leukemia (ALL) (3 BMs and 5 PBMNCs); myelodysplastic syndromes (MDSs) (20 BMs and 6 PBMNCs); and
aplastic anemia (1 BM). The French-American-British classification of
AML and MDS is presented here, along with an enumeration of the numbers
and types of samples we obtained for each: M1, undifferentiated (4 BMs
and 3 PBMNCs); M2, myeloblastic (6 BMs and 3 PBMNCs); M3, promyelocytic
(6 BMs); M4, myelomonocytic (6 BMs and 6 PBMNCs); M5a, poorly
differentiated monoblastic (3 BMs and 1 PBMNC); M5b, well-differentiated monocytic (4 BMs and 5 PBMNCs); M6, erythroleukemia (7 BMs); refractory anemia (RA) (3 BMs); RA with ring sideroblasts (RARS) (4 BMs); RA with excess blasts (RAEB) (8 BMs and 4 PBMNCs); RAEB
in transformation (RAEBT) (5 BMs and 2 PBMNCs). As controls, 8 nonmalignant BM (idiopathic thrombocytopenic purpura, iron deficiency anemia, and normal BM) and 6 normal PBMNC samples were also analyzed. The semiquantitative RT-PCR was performed essentially as previously described.17 Primers and cycle numbers were as follows:
for TfR1, primers 5'-AGGAACCGAGTCTCCAGTGA-3' and
5'-ATCAACTATGATCACCGAGT-3', 22 cycles; for TfR2-, primers
5'-GTGGTCAGTGAGGATGTCAA-3' and 5'-CCACACGTGGTCCAGCTTCTGGCGGGAG-3', 22 cycles; for TfR2-, primers 5'-ACGTCTCTGGCATCCTTCC-3' and
5'-TGTAGGGGCAGTAGACGTCA-3', 25 cycles; for glyceraldehyde-3-phosphate
dehydrogenase (GAPDH), primers 5'-TACATGGCTGGGGTGTTGAA-3' and 5'-AAGAGAGGCATCCTCACCCT-3', 13 cycles. The PCR products were transferred to nylon membranes
after agarose gel electrophoresis and hybridized with
32P-labeled cDNAs, and the ratio of band intensities of
TfR1, TfR2-, and TfR2- versus GAPDH were calculated with the use
of a densitometer.
Other methods Northern blot analysis was performed by means of TfR1, TfR2, and GAPDH cDNA probes and standard protocols.4,18 Statistical analysis was performed by means of unpaired Student t test.
Expression of TfR2 mRNA in hematopoietic cell lines Our previous study showed that high levels of TfR2 expression occurred in K562, an erythroid leukemia cell line derived from a patient with CML, whereas expression of TfR2 mRNA was not detectable in the myeloid cell lines KG-1, U937, and HL-60 by a standard Northern analysis.4 To examine whether TfR2 expression is specific for erythroid cells in the hematopoietic system, we performed Northern analysis using a variety of hematopoietic cell lines, including 4 erythroid cell lines: HEL-R, KU-812-F, OCI-M1, and K562. Among the cell lines that we tested, all of the erythroid cell lines expressed high levels of TfR2 mRNA, while all the lymphoid (Raji and MOLT-16) and myeloid (U937, NB4, HL-60, KCL22, and KG-1) cell lines expressed either low or undetectable levels of TfR2 mRNA (Figure 1). In contrast, TfR1 expression was detectable in all the cell lines that we tested, though levels of TfR1 mRNA expression were very high in OCI-M1 cells and were relatively low in Raji, U937, HEL-R, and K562 cells (Figure 1).
Immunohistochemical staining of TfR2-transfected CHO-TRVb and normal BM cells To examine if expression of TfR2 is lineage specific among hematopoietic cells, we used the immunohistochemical technique. First we tested our anti-TfR2 antibody for this technique using CHO-TRVb cells that had been stably transfected with either TfR1 or TfR2-. Cytospin specimens of
neomycin-resistant control cells as well as TfR1-transfected and
TfR2--transfected cells were incubated with 50-fold diluted
anti-TfR2 antiserum or the same concentration of normal rabbit serum
and were immunohistochemically stained (Figure
2A-D). TfR2-transfected cells stained
strongly, especially on their cell surfaces (panel B as compared with
panel A), whereas neomycin-resistant control cells and TfR1-transfected cells stained only at background levels (Figure 2C and 2D,
respectively). These results prompted us to examine normal BM
mononuclear cells using this technique. Low levels of staining occurred
in both erythroid and nonerythroid cells with nonimmune rabbit serum
(Figure 2E), but the majority of erythroblasts clearly stained with the anti-TfR2 antibody at more than the background levels (Figure 2F). Some
of the erythroid cells at the late stages of differentiation as well as
mature erythrocytes did not stain clearly with the anti-TfR2 antibody.
Most of the myeloid cells that we examined were negative for TfR2,
although we could not distinguish eosinophils and basophils from
neutrophils with this staining. A few large cells on the cytospin
specimens were probably megakaryocytes, and some of them were positive
for TfR2 (Figure 2G).
Expression of TfR2 mRNA in cultured normal erythroid cells Human erythroid cells at various stages of differentiation were analyzed for expression of TfR1 and TfR2 mRNA by real-time Q-PCR. We prepared 3 erythroid cell populations from normal peripheral blood: CD34+/d4, GPA+/d4, and GPA+/d10. The CD34+/d4 cells represent mostly immature erythroid progenitors. The GPA+/d4 cells were CD36+ and CD34 by flow-cytometric
analysis, indicating that these cells were at either the erythroid
colony-forming unit or the erythroblast stage. The results from Q-PCR
are shown in Figure 3A. Levels of TfR1 mRNA dramatically increased during erythrocytic
maturation between GPA+/d4 and GPA+/d10, while
TfR2 mRNA gradually decreased during erythroid
differentiation. The primers that we used for TfR2 could
amplify both and forms, although our
previous study indicated that the majority of TfR2 transcripts in erythroid cell lines were the form. To confirm the
expression profile of the transcripts during normal
erythroid differentiation, we designed another set of primers that can
amplify only the form. For this analysis, CD34+/d4
cells were cultured in the presence of erythropoietin, and the cells
were harvested at days 4, 6, 7, 10, 14, and 18. The cells harvested at
day 6 expressed CD36 and GPA but not CD34, so this population was the
equivalent of the population of GPA+/d4 in Figure 3A. The
cells harvested at day 10 expressed both GPA and CD71, and these cells
were the equivalent of the GPA+/d10 cells in Figure 3A.
Results of quantitative RT-PCR shown in Figure 3B demonstrated that, in
agreement with our first analysis, the levels of TfR2-
transcript declined as the erythroid progenitors matured.
Expression of TfR2 mRNA in BM and PBMNCs from patients with hematological disorders We analyzed 107 samples from 90 individuals with leukemia and preleukemia together with 8 nonmalignant BM and 6 normal PBMNC samples for expression of TfR1, TfR2-, and TfR2-
mRNAs. Some of the samples were taken serially from the same patients
during disease progression. Expression levels of TfR2-
were higher in nonmalignant BM samples than in normal PBMNC samples
(P = .038; Figure 4A, shaded
bars). Among the BM samples, levels of TfR2- expression
in M6 were clearly higher than those of nonmalignant BM samples
(P = .247; Figure 4A). High levels of expression of TfR2- (greater than 60% of K562) occurred in 13 samples:
1 M2-BM, 4 M6-BM (erythroleukemias), 1 CML-BM, 2 RARS-BM, 2 RAEB-BM, 1 RAEBT-BM, 1 M1-PB, and 1 CML-PB.
Differential cell counts of the BM were available from 9 of the 11 BM
samples that showed high levels of TfR2-
The profile of TfR2-
Among the hematological cell lines that we tested, high levels of TfR2 occurred only in erythroid cell lines (Figure 1). This suggests that expression of this gene may be selective to the erythroid lineage of hematopoietic cells. This idea was supported by our immunohistochemical staining of normal BM cells using anti-TfR2 antibody, in which a majority of erythroblasts, but not myeloid cells, were clearly stained. These results are consistent with our previous study that showed enhancement of murine TfR2 promoter activity by GATA-1.6 GATA-1 is highly expressed in erythroid cells as well as in megakaryocytes, eosinophils, and mast cells, and the putative GATA-1-binding sites of TfR2 are well conserved between human and mouse. We observed a few large cells, probably megakaryocytes, that were positive for TfR2 staining (Figure 2G). However, expression of TfR2 in megakaryocytes, eosinophils, and mast cells still remains to be studied, because the numbers of these cells in our materials were very small and we could not distinguish eosinophils from neutrophils in our immunohistochemical staining method. In the leukemic and preleukemic BM samples, levels of TfR2
mRNA roughly correlated with the proportion of erythroid cells in the
marrow. High levels of TfR2- In MEL cells, we have shown that expression of TfR2
decreased and TfR1 increased during dimethyl
sulfoxide-induced erythrocytic differentiation.6 Similar
expression profiles were observed in normal human erythroid cells as
they differentiated in vitro in the presence of erythropoietin (Figure
3). The CD34+ erythroid precursors expressed high levels of
TfR2 and very low levels of TfR1 mRNAs. During
their differentiation, levels of TfR2 mRNA decreased
gradually and expression of TfR1 mRNA increased dramatically
(Figure 3B). TfR2 has at least 2 transcripts, We have shown that TfR2- Recently, Camaschella et al20 and Roetto et
al21 reported on patients with hereditary
hemochromatosis from 4 families, who had homozygous nonsense mutations
(Tyr250Xaa, Glu60Xaa, or Met172Lys) of the TfR2 gene. Both
Tyr250Xaa and Met172Lys mutations affect both the From the current study, we believe that TfR2 may be a useful marker for early erythroid cells. We also identified several myeloid, nonerythroid leukemia cases in which levels of expression of TfR2 were relatively high. Expression of TfR2 may have some relevance to clinical features of these cases. Functional significance of the TfR2 gene in hematopoietic cells remains to be delineated by study of TfR2-deletional mice.
We thank Drs T. McGraw, J. Minowada, M. Lanotte, I. Miyoshi, and T. Papayannopoulou for providing us with valuable cell lines and K. Yoshida (Kanazawa Medical University) for his technical assistance.
Submitted September 27, 2000; accepted June 29, 2001.
Supported in part by grants from National Institutes of Health, C. and H. Koeffler Foundation, Horn Foundation, Parker Hughes Trust, Ko-So Foundation and Kanazawa Medical University (S00-2); H.P.K. holds the Mark Goodson endowed chair of Oncology at Cedars-Sinai Medical Center and is a member of the Jonsson Cancer Center of University of California-Los Angeles.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: H. Phillip Koeffler, The Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Burns and Allen Research Institute, UCLA School of Medicine, Los Angeles, CA 90048.
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  D. F. Wallace, L. Summerville, E. M. Crampton, and V. N. Subramaniam Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis Am J Physiol Cell Physiol, February 1, 2008; 294(2): C383 - C390. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
