Induction of differentiation of WEHI-3B D+ leukemic cells transfected

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Induction of differentiation of WEHI-3B D+ leukemic cells transfected
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Induction of Differentiation of WEHI-3B D+ Leukemic Cells Transfected
With Differentiation-Stimulating FactodLeukemia
Inhibitory Factor Receptor cDNA
By Mikio Tomida
exDifferentiation-stimulating factor (D-factor)/leukemia inhibi- exhibited the ability to reduce nitroblue tetrazolium and
pression of the differentiation antigenMac-l (CD11b) on the
tory factor can induce the differentiation of mouse myeloid
cell surface increased. The effect of
c y t o k h , which induce
leukemia M1 cellsandalso stimulate proliferation of the
the differentiation of M 1 cells, on the transfected WEHI-BB
interleukin-3 (IL3)-dependentcell line, DA-la. To determine
cellswasexamined.Thesensitivity
to oncostatin M was
whether D-factor can inducethe differentiation of leukemia
identical to that against D-factor in the cells of each clone.
cells other than M 1 cells, WEHI-3B D+ mouse myelomonoExpression of D-factor receptor in WEHI-BB cells promoted
cytic leukemia cells were transfected with a plasmid containing mouse D-factor receptor cDNA. Expression of D-fac- sensitivity to 11-6 and granulocyte colony-stimulating factor
tor receptor in transfected cells was determined by binding (G-CSF). Induction of differentiation of the cells accompanied the suppression of proliferation.Treatment of the cells
of['25]D-factorandanalyzedbyScatchard's
method. The
with D-factor for longer than 5 days resulted in50% inhibitransfected cells had high-affinity D-factor receptorswith a
dissociation constant of 100to 200 pmol/L and binding sites tion of growth. These results indimto that the stimulating
effect of D-factor onthe dflerentiation of malignantmyeloid
per cell varied from 67 to 1,500 among several clones. The
cells is not unique to M1cells.
cells expressing a high level of D-factor receptor were in0 7995 by The AmericanSociety of Hematology.
duced to differentiate by D-factor; about 60% of the cells
W
E AND
purified and cloned differentiation-stimulating factor (D-factor)/leukemia inhibitory factor as a cytokine inducing differentiation of mouse
myeloid leukemia Ml-T22 cells into macrophages. We
found recently that injections of recombinant mouse D-factor
prolonged the survival times of mice implanted with the M1T22 cells4 and that human D-factor suppressed the proliferation of freshly isolated leukemic blast cells from acute
myeloblastic leukemia patient^.^ These results suggest that
D-factor is of potential value in the therapy of myeloid leukemia. However, D-factor stimulates the proliferation of some
leukemic cell lines, such as mouse DA-la6 and human TFl.' Furthermore, it has a wide variety of biologic activities
besides its actions on normal and leukemic hematopoietic
cek8
Gearing et a193L0
isolated a cDNA for human D-factor receptor and proved that D-factor receptor associates the IL6 signal transducer, gp130. Oncostatin M (OSM) and Dfactor share a common receptor complex and receptors for
IL-11 and ciliary neurotrophic factor (CNTF) also share
gp130." The existence of a common signal transduction
pathway, mediated through gp130, may explain the functional redundancy of D-factor, OSM, IL-6, IL-11, and CNTF.
To determine whether D-factor can induce the differentiation of leukemic cells other than Ml-T22 cells, we cloned
a cDNA encoding mouse D-factor receptor" and introduced
the D-factor receptor into WEHI-3B D+ mouse myelomonocytic leukemia cells, which were induced to differentiate by
IL-6 or granulocyte colony-stimulating factor (G-CSF), but
not D - f a ~ t o r . ' ~We
. ' ~ show here that D-factor and OSM induce differentiation and suppress proliferation of WEHI-3B
D+ cells transfected with D-factor receptor cDNA.
MATERIALS AND METHODS
Cells and cell culture. WEHI-3B D+ leukemia cells (kindly provided by Dr Alan C. Sartorelli, Yale University School of Medicine,
New Haven, CT) were cultured in McCoy's 5A modified medium
(GIBCO-BRL, Grand Island, NY) supplemented with10% (v&
vol) heat-inactivated fetal calf serum (FCS; GIBCO BRL or Flow
Laboratories, Stanmore, Australia) in an atmosphere of 5% CO2 in
air at 37°C. Myeloid leukemic M1 cells were cultured as described
Blood, Vol 85, No 1 (January l),1995: pp 217-221
previously.' Clone T-22 cells can be induced to differentiate by Dfactor, but clone R-4 cells can not.
Cytokines. Recombinant mouse D-factor was produced in Chinese hamster ovary cells and recombinant human G-CSF was produced in Escherichia coli and purified to homogeneity as described
p r e v i o ~ s l y . ~ .Recombinant
~~.'~
human IL-6 was kindly provided by
Ajinomoto CO (Kawasaki, Japan). Recombinant human OSM and
IL- 11 were purchased from R & D Systems, Minneapolis, MN.
Plasmid construction. Mouse cDNAs encoding the membrane
receptor and the soluble receptor for D-factor were cloned from a
cDNA library prepared from the liver of a pregnant mouse as described previously.12The full length of cDNA encoding the membrane receptor was prepared by recombination of the LS 1 clone and
LS3 clone (in Fig 2A of reference 12) at the Tthl11I restriction site.
The cDNA was subcloned into the Eco R1 site of the expression
vector, pSG5 (Stratagene, La Jalla, CA), which includes the SV40
early promotor. It was confirmed that the cDNA was functional, by
transient expression of the cDNA in COS-7 cells. The binding of
['ZSI]D-factorto COS-7 cells increased 80-fold after transfection of
the cDNA into the cells.
Transfection of DNA. DNA was introduced into WEHI-3B cells
by electroporation using the Gene Pulser (Bio-Rad Laboratories,
Richmond, CA). The cells (1 X 10') were suspended in 0.8 mL of
HEPES-buffered saline (50 mmol/L HEPES, 137 mrnoi/L NaCI, 6.8
mmoVL KCI, 0.28 mmoVL Na2HP04,and 0.1% dextrose, pH 7.1)
containing 20 pg of linearized expression plasmid and 1 pg of pXTl
(Stratagene) conferring neomycin resistance, and incubated on ice
for 15 minutes. The cells were exposed to a 450 V pulse with a
capacitance of 960 pF, and returned to ice. After incubation on ice
From Department of Chemotherapy, Saitama Cancer Center Research Institute, Saitama, Japan.
Submitted May 19, 1994; accepted September 14, 1994.
Supported by a Grant-in-Aid
for Scientific Research on a Priority
Areafrom the Ministry of Education. Science and Culture of Japan.
Address reprint requests to Mikio Tomida, PhD, Saitama Cancer
Center Research Institute, lna, Saitama 362, Japan.
The publication costs of this article were defrayed in parr 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 1995 by The American Society of Hematology.
0006-4971/95/8501-0030$3.00/0
217
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218
MlKlOTOMIDA
Table 1. D-Factor Binding and D-Factor-Dependent Differentiation
of WEHI-BB Cells Transfected With D-Factor Receptor cDNA
NBT-Reducing Cells (%)
Clone
DR1
DR2
DR3
DR4
DR5
DR6
DR7
DR8
Neo
M1-T22
M1-R4
D-Factor
Binding (cprn)
12,016 f 145*
15,851 2 411
1,565 f 83
4,165 f 74
923 t 1
2,008 f 59
1,574 2 12
630 2 37
-14 2 15
4,014 f 216
2,047 f 90
- D-Factor
+ D-Factor
6.7 f 2.7
5.6 2 2.4
0.5 t 0.5
1.5 t 1.5
62.8 2 7.0
58.2 f 8.2
2.5 2 0.5
62.3 f 5.8
21.8 2 2.3
55.4 f 5.3
35.0 f 10
2.5 t 0.5
2.5 f 0.5
8.5 f 1.5
6.0 ? 2.0
0.5 ? 0.5
0
ND
ND
0.5 f 0.5
ND
ND
Cells (lo6 in 0.5 mL) were incubated withI'2511D-factor (5 ng) for
3 hours atroom temperature. Specific binding was determined by
subtracting the binding in the presence of 60-fold excess of unlabeled
D-factor.NBT-reducing cells were determined by the microscopic
assay after treatment of the cells with or without 10 kg/mL of D-factor
for 3 days.The cells were treated with D-factorthe next day on which
D-factor binding was determined.
Abbreviation: ND, not determined.
* Each value is the mean of duplicate determinations f SE.
for 5 minutes, the cells were cultured in 20 mL medium for 2 days.
The cells were transferred into 96-well plates and cultured in medium
containing G-418 at the final concentration of 2 mg/mL.
Cellular binding of ['2'r]D-factor. Iodination of mouse D-factor
with chloramine-T and assay of cellular binding of [12SI]D-factor
were performed as described previously.'6 The specific radioactivity
of the [lZ'I]D-factor preparation was 3.4 X 10' counts per minute
(cpm)/ng protein.
Properties of differentiated cells. The ability of cells to reduce
nitroblue tetrazolium (NBT) was used as a functional marker of
differentiation. Cell numbers were determined using a Model ZM
Coulter Counter (Coulter Electronics, Luton, UK). One X lo6 cells
were incubated in 1 mL of serum-free medium containing 0.1%
NBT and 100 ng/mL of 12-0-tetradecanoylphorbol 13-acetate at
37°C for 30 minutes. In the microscopic assay, the percentage of cells
with blue-black formazan deposit was determined by examination of
a minimum of 200 cells. In the colorimetric assay, the reaction was
stopped by adding HCl to the final concentration of 1 m o a . The
suspension was centrifuged and the formazan deposits were solubilized by adding dimethyl sulfoxide. The absorption of the formazan
solution at 560 nm was measured with a spectrophotometer (U-2000,
Hitachi, Tokyo).
Expression of the granulocyte- and macrophage-specific antigen
Mac-l (CD1 lb) on the cell surface was determined by indirect immunofluorescent staining and flow cytometry as described previously." The cells (2 X 10') were washed with phosphate-buffered
saline (PBS) and incubated in 50 p L of rat anti-Mac-l monoclonal
antibody (diluted 1:20; Boehringer Mannheim Biochemica, Indianapolis, IN) in PBS containing 0.1% bovine serum albumin (BSA)
on ice for 30 minutes. Then the cells were washed and stained in
50 pL of phycoerythrin-conjugated goat-antirat IgG antibody (diluted 1:20; Cedar Lane, Ontario, Canada) in PBS containing 0.1%
of BSA on ice for 30 minutes. The cells were washed, then analyzed
in an Epics Elite flow cytometer (Coulter Electronics).
induce differentiation in mouse WEHI-3B leukemic colonies." Because the cells do nothave D-factor receptors,
D-factor receptor cDNA was introduced into the cells to
determine the general effects of D-factor on leukemic cells.
Mouse D-factor receptor cDNA was transfected into WEHI3B cells, together with a plasmid carrying theneomycin
resistance gene. G-418-resistant transformants weretested
for the ability to bind [1251]D-factor,
and several independent
clones were isolated (Table 1). Neo cells were transfected
with the neomycin resistance gene alone and did not express
D-factor binding sites. The specific binding of D-factor to
two clones of M1 cells is also shown in Table 1. Ml-T22
cells differentiate in response to D-factor, whereas M1-R4
cells do not respond to the cytokine. The properties of the Dfactor binding to these stable transformants were examined.
Clones of DR2 and DR8 were incubated with ['251]D-fa~tor
at various concentrations. Figure 1 shows the binding characteristics of D-factor to DR2 cells. Scatchard analysis showed
that the cells have 1,500binding sites per cell with a dissociation constant of 111 pmoVL. The number of D-factor receptors expressed in clone DR8 was67 sites per cellwith a
dissociation constant of 207 pmoVL (data not shown).
Effects of cytokineson the prol.$erution und differentiation
of the transfected cells. The relationship between the ability of cells to reduce NBT and the specific ['251]D-factor
binding capacity of the transfected WEHI-3B cells was examined. The cells were incubated with or without D-factor
one day after the assay of D-factor-binding of the cells. After
3 days of incubation, the number of cells and the ability
of the cells to reduce NBT, a differentiation marker, were
determined. Similar results were obtained from three independent experiments, and a typical result from one experiment was summarized in Table 1. The increased expression
of the receptor resulted in enhancement of the ability of the
cells to differentiate. However, no strict relationship existed
between the degree of differentiation and the D-factor binding capacity of the cells. For example, although both clones
had a similar D-factor binding capacity, clone DR6, but not
clone DR3, responded to D-factor.
As another marker of differentiation, Mac-l antigen on
'*51-D-factor(PM Y 10')
'251-D-tactorbund (PM)
RESULTS
Establishment of cell lines expressing the D-factor receptor. Both G-CSF and IL-6, but not D-factor, were able t o
Fig 1. Binding of ['"ID-factor to DR2 cells. (AI Specific binding of
['251D-factorto cdls incubated at increasing concentrations of the
radiolabeledligand. (B) Scatchard plot of the binding data.
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EXPRESSION OFD-FACTORRECEPTOR
219
ON WEHI-3B
entiate by OSM. Effects of various concentrations of Dfactor or OSM on clones DR1 and DR2 were examined.
Figure 4 shows both D-factor and OSM induced the differentiation of DR1 cells in a similar dose-dependent manner.
Both cytokines were effective at concentrations higher than
0.5 ng/mL. The stimulating effects of both cytokines were
saturated at concentrations lower than 5 ng/mL. K-6, IL- 1 1,
and G-CSF were more effective at the concentration of 100
ng/mL than at 10 ng/mL (data not shown).
DISCUSSION
.l
1
100
10
1000
Fluorescence intensity
Fig 2. Expression of Mac-l antigen on DR1 cells treated with Dfactor. (A) Cells were treated with 10 n g h L of D-factor for 6 days,
then stained with monoclonal anti-Mac-? and phycoerythrin-conjugated goat-antirat IgG antibody. (B) Untreated cells. IC) Untreated
cells stained with the antirat IgG alone.
the cell surface was determined by flow cytometry. Although
parental WEHI-3B cells and untreated DRl cells expressed
a low level of Mac-l antigen, the expression of the antigen
on DRl cells increased after exposure of the cells to Dfactor (Fig 2).
The induction of differentiation of the transfected cells
accompanied a decrease in cell number. The cell number of
clones DR1, DR2, DR4, and DR6 treated with D-factor for
3 days was 70% to 80% of that of the control culture. The
growth rates of clones DR3, DR8, and Neo were not changed
by treatment of the cells with D-factor. Figure 3 shows the
effect of D-factor on proliferation of DR2 cells. Treatment
of the cells with D-factor for longer than 5 days resulted in
50% inhibition of growth. A similar inhibitory effect of Dfactor on the proliferation of DR1 cells was observed (data
no shown).
Next, the effects of several cytokines, which induced differentiation of mouse myeloid leukemia M1 cells, on the
WEHI-3B cells transfected with D-factor receptor cDNA
were examined. Results are shown in Table 2. DRl, DR2,
and DR6 are D-factor-sensitive clones, whereas DR8, Neo,
and parental WEHI-3B are not. All clones responded to IL6. IL-6 is the most effective inducer against parental WEHI3B and the cells transfected with neomycin resistance gene
alone (Neo). Parental WEHI-3B cells responded poorly if at
all to the inducing activity of G-CSF in liquid culture as
reported byLi et
Some clones, which responded to Dfactor, were more sensitive to G-CSF, as compared with the
parental cells. The sensitivity to IL-l1 wasvaried among
these clones. The sensitivity to OSM was identical to that
against D-factor in the cells of each clone. The growth inhibition was also observed in clones that were induced to differ-
WEHI3B cells transfected with D-factor receptor cDNA
were induced to differentiate by treatment of the cells with
D-factor or OSM. Recently, Gearing et a l l 9 reported that
cotransfection of D-factor receptor cDNA and gp130 cDNA
into the IL-3-dependent pro-B cell line, BAF-B03, resulted
in D-factor- and OSM-induced proliferation. These results
confirmed that D-factor can both induce differentiation and
stimulate proliferation, depending on the cell line. BAFB03 cells, but not WEHI-3B cells, required cotransfection
of gp130 cDNA. This discrepancy comes from the difference
in the expression of endogenous gp130 in both cell lines.
Parental WEHI-3B cells respond to IL-6 and the cells
transfected with D-factor receptor cDNA alone express high
affinity D-factor receptors, indicating the expression of endogenous gp130 in WEHI-3B cells.
All three transfected WEHI-3B clones, which expressed
a higher number of D-factor receptors than those of Ml-T22
cells, were sensitive to D-factor (Table 1). On the other
hand, all transfected clones examined, which showed lower
capacity of D-factor-binding than that of DR8 clone, could
not be induced to differentiate by D-factor (data not shown).
Therefore, the level of D-factor receptor expression in these
leukemia cells seemed to be important for a response to D-
i
1
OO
1
2
3
4
5
6
Days of treatment
Fig 3. Suppression by D-factor of the proliferation ofDR2 cells.
Cells were seeded at 5 x 10‘ cellslmL and culturedwith (0)or without (0)10 ng/mL of D-factor. Cell numbera were determined daily
using a Coulter Counter. On day 3, the cultures were diluted with
fresh medium to maintain growing phase. Points andbars are means
? SE for duplicate determinations. Anotherexperiment gave similar
results.
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MlKlO TOMIDA
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Cells were e x p o d to various concentrationsof D-factor (0)
or OSM
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factor. However, a borderline of D-factor binding capacity
in determination of D-factor responsiveness was not clearcut. Variability in D-factor responsiveness in the transfected
clones was observed. The result suggests that the number of
the receptor alone does not determine the ability of differentiation of the cells. Alternatively, it is possible that the degree
of expression of D-factor receptor varied during the experiments, although the assay of D-factor binding and the differentiation of the cells were performed within several days.
The expression of the receptor on the transfected cells continued for more than 1 month after the isolation of the clones,
but the degree of the expression fluctuated during long-term
culture. Li et all8 also reported that the increased expression
of G-CSF receptor in WEHI-3B cells transfected with the
receptor cDNA resulted in the induction of differentiation
of the cells in liquid culture.
We previously showed that D-factor is a potent inducer
of differentiation of Ml-T22 cells and that G-CSF is a weak
inducer for the cells.'.15Combination of G-CSF with D-factor
resulted in synergistic stimulation of differentiation?" IL-6
andOSM also induced differentiation of Ml-T22 cells."
Although IL-l1 and IL-6 showed the same effect in many
cases, IL-11 did not induce the differentiation of the cells
(unpublished results, December 1992). Rose andBruce"
compared the structure of the proteins and genes of D-factor,
OSM, IL-6, and G-CSF and suggested that these four cytokines have evolved from a common ancestor and are members of a single cytokine family. Furthermore, receptors for
D-factor, OSM, IL-6, and IL-11 share a signal transduction
subunit, gp130." On the other hand, IL-6 and G-CSF, but
not D-factor, induce the differentiation of parental WEHI-3B
cells.'-7314
Transfected WEHI-3B cells with D-factor receptor
cDNA respond to D-factor, OSM, IL-6, and G-CSF (Table
2). Some transfected clones, but not all clones, responded
to IL- 11.Expression of D-factor receptor in WEHI-3B cells
promoted the sensitivity to L - 6 and G-CSF and a small
portion of these cells had the ability to reduce NBT in the
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EXPRESSION
OF D-FACTORRECEPTOR ON WEHI-3B
absence of treatment of any cytokines (Table l). These reaIt is possible thatthat FCS
sons areunknownatpresent.
containsalow level of D-factoror OSM andthat these
cytokinesstimulatedifferentiation of the WEHI3B cells
synergistically withG-CSF or XL-6.It was shownthat induction of differentiation of Ml-T22 cells byIL-6 or G-CSF
increased in the presence of a low concentration of D-facAlthough D-factor at 0.5 ng/mLinduceddifferentiation
and suppressed proliferationof Ml-T22 cells, other leukemic
cell lines, such as HL-60 and U-937, respond poorly to Dfactor?' Werecently showed thatD-factorsuppressedthe
proliferation of freshlyisolatedleukemicblast
cells from
acutemyeloblasticleukemia
patient^.^ Thepresentstudy
showed that D-factor inhibited the proliferation
of WEHI3B cells if they expressed an adequate number of D-factor
receptors.Theseresultsindicate
thatD-factorsuppresses
proliferation of various myeloid leukemia cells.
ACKNOWLEDGMENT
We thank Dr Moriaki Hayashi of the Saitama Cancer Center
Research Institute for his help in the flow cytometry measurements
and preparation of the manuscript.
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From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
1995 85: 217-221
Induction of differentiation of WEHI-3B D+ leukemic cells transfected
with differentiation-stimulating factor/leukemia inhibitory factor
receptor cDNA
M Tomida
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