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Medizinische Klinik III/Abteilung Hämatologie, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt, Germany [E. P., S. G., N. B., D. H., O. G. O., M. R.], and Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia University, 06100 Perugia, Italy [A. O.]
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ABSTRACT |
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. Hence, we reasoned
that As2O3 might have a selective inhibitory
effect on proliferation of BCR-ABL-expressing cells. Here, we report that: (a) As2O3 induced apoptosis in Ph+ but not in Ph- lymphoblasts; (b) enforced expression of BCR-ABL in U937 cells dramatically increased the sensitivity to As2O3; (c) the effect of As2O3 was independent of BCR-ABL kinase activity; and (d) As2O3 reduced proliferation of chronic myelogenous leukemia blasts but not of peripheral CD34+ progenitors. In summary, these data establish As2O3 as a tumor cell-specific agent, making its clinical application in Ph+ leukemia feasible.
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Introduction |
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Recently, it has been reported that
As2O3 is capable of
inducing complete remissions in patients with t(15;17) APL
(4, 5, 6)
. The response to
As2O3 in APL patients is
genetically determined by expression of the PML/RAR
fusion protein specific for t(15;17). Furthermore, transfection of
PML/RAR into naturally
As2O3-resistant U937 cells
renders these cells sensitive to
As2O3-induced apoptosis
(7)
.
Therefore, we investigated whether there is also a functional relationship between the expression of the translocation product BCR-ABL and As2O3-induced apoptosis in Ph+ leukemia.
Here, we show that As2O3
induced apoptosis in Ph+, but not in Ph- lymphoblastic cell lines.
BCR-ABL mediated
As2O3-induced apoptosis,
analogous to PML/RAR. This activity was independent of
the aberrant kinase activity of BCR-ABL.
As2O3 was effective on Ph+
peripheral blasts of patients with CML in blast crisis but did not
influence colony formation activity of primary
CD34+ hematopoietic precursors.
The presented data establish the basis for the application of As2O3 as a tumor cell-specific agent in the treatment of Ph+ CML, as well as Ph+ ALL.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-positive P/R9 cells were obtained as
described previously (8
, 9)
. The p185
(BCR-ABL) and p210
(BCR-ABL) encoding cDNA was cloned into the
ZnSO4 (Zn2+)-inducible
pGMTSVneo expression vector (9)
. The
BCR-ABL-positive U937 MTp185 and MTp210 bulk populations
were obtained by electroporation of these p185
(BCR-ABL)- and p210
(BCR-ABL)-carrying expression vectors and G418
selection. The expression of the exogenous protein by
Zn2+ treatment was induced as described
(9)
and evaluated by Western blotting. Anti-ABL
antibody (-ABL), anti-bcl-X
(-bcl-X), and anti-PARP (-PARP)
were purchased from Santa Cruz Biotechnology (Santa Cruz, CA);
anti-bcl-2 (-bcl-2) from DAKO (Hamburg,
Germany); and anti-phosphotyrosine (-PY) from Upstate Biotechnology,
Inc. (Lake Placid, NY). All were applied according to widely used
protocols.
Apoptosis Assay.
Zn2+-treated U937 cells were washed twice
with PBS to eliminate Zn2+, thus avoiding
interference with apoptosis. All cell types were diluted to 1 x 105 cell/ml and exposed to a final
concentration of 0.1–2 µM
As2O3 (Sigma Chemical Co.,
St. Louis, MO). For analysis of the rate of apoptosis, the FACS-based
7-AAD method was used as described elsewhere (7)
.
Patient Samples.
Fresh CD34+ progenitor cells were purified from leukapheresis samples
after 4–5 days of mobilization with granulocyte colony-stimulating
factor (10 µg/kg body weight) of two patients with Ph+ ALLs in CR.
The CML blasts derived from the peripheral blood of two patients with
newly diagnosed myeloid or lymphatic blast crisis. CD34+ cells were
isolated by Ficoll-Hypaque density-gradient centrifugation, followed by
separation with the VarioMACS system, with the appropriate columns
using the Direct CD34+ Progenitor Isolation Kit according
to manufacturer’s instructions (Myltenyi Biotec, Bergisch-Gladbach,
Germany).
Methyl-Cellulose Assay.
Fresh CD34+ cells and CML PMNCs were plated at 400 cells/ml on day 2 of
treatment with As2O3, in
0.9% semisolid methyl-cellulose Methocult complete medium (StemCell
Technologies Inc., Vancouver, Canada) and incubated at 37°C in a
humidified atmosphere of 5% CO2. Each assay was
plated as triplicate. After 9–14 days of incubation colonies (>50
cells) were counted.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-expressing NB4 and U937 cells (4
, 7)
, we exposed different ALL- and CML-derived lymphoblastic cell
lines to 2 µM
As2O3. SD-1, Tom-1, and
Sup-B15 cells are p185(BCR-ABL)-positive ALL cell
lines, and BV173 is a p210(BCR-ABL)-positive CML
cell line (10)
. As control, we used Ph- lymphoblastic
cell lines such as Nalm-6 (B-lineage ALL), MOLT-3 (T-lineage ALL), SEM
[t(4;11)-positive B-lineage-ALL], Jurkat (leukemic T-cell lymphoma),
and Daudi (Burkitt lymphoma). Fig. 1A
depicts the BCR-ABL protein expression levels of
the above cited cell lines. The rate of apoptosis was determined by
FACS analysis, measuring the percentage of 7-AAD-positive cells after
72–96 h of As2O3 exposure
(11)
. In Fig. 1B
, we show one representative
experiment of three that gave similar results. In contrast to untreated
cells (BV173, 16%; SD-1, 16%; Sup-B15, 26%; Tom-1, 35%) all Ph+
lymphoblastic cell lines showed a high rate of apoptosis on treatment
with As2O3 (BV173, 74%;
SD-1, 49%; Sup-B15, 93%; Tom-1, 79%). None of the Ph- cell lines
exhibited a significant response to the
As2O3 treatment (Fig. 1B
). No average was calculated because the kinetics of
apoptosis in the Ph+ cell lines differed between separate experiments,
resulting in considerable variability, in particular, at the early time
points. Moreover, in contrast to Ph- cells, none of the Ph+ cell lines
recovered from treatment with
As2O3 in prolonged culture
(data not shown).
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demonstrates a typical 7-AAD FACS profile of BV173
cells exposed to increasing concentrations of
As2O3. Already, 0.1
µM
As2O3 induced a significant
rate of apoptosis with respect to untreated cells. Furthermore,
activity of As2O3 was dose
dependent, as demonstrated by an increased percentage of apoptotic
cells with rising dosages of
As2O3.
Taken together, these data indicate a specific activity of
As2O3 in
BCR-ABL-expressing lymphoblastic cell lines comparable with
the known activity of As2O3
on PML/RAR-positive cells. Moreover,
As2O3 exerts its effect on
Ph+ cells, regardless of the type of product of t(9;22) present
[i.e., the ALL-specific p185(BCR-ABL)
is able to mediate sensitivity to
As2O3 to the same extent as
the CML specific p210(BCR-ABL) ].
As2O3-induced Apoptosis in Ph+ Cells Is
Genetically Determined by the Presence of t(9;22).
To examine whether
As2O3-induced apoptosis in
Ph+ cell lines is specifically mediated by BCR-ABL, and to
exclude the possibility that the effect of
As2O3 is due to a yet
unknown common feature of the different Ph+ cell lines, we transfected
U937 cells with different expression vectors. The expression vectors
contained cDNA encoding either p185(BCR-ABL) or
p210(BCR-ABL) under the control of the
Zn2+-inducible metallothionein (MT-1)
promoter (9)
.
U937 cells are myeloid precursors blocked at the promonocytic stage,
which do not undergo
As2O3-induced apoptosis
(4
, 7)
. In our experiments, we analyzed the effect of
As2O3 on
p185(BCR-ABL)- and
p210(BCR-ABL)-expressing U937 cells. To avoid the
bias of clonal variability, we used highly expressing bulk populations
selected after transfection only for G418 resistance without further
subcloning (MTp185 and MTp210). On Zn2+ induction
the transfected cells expressed the BCR-ABL fusion proteins
to a similar level as BV173, SD-1, Sup-B15, and Tom-1 cells (Fig. 1A
). As negative control for
As2O3-induced apoptosis we
used the MT B45 cells, transfected with the "empty" expression
vector, and as positive control we used the
PML/RAR-expressing P/R9 cells, as described previously
(7)
. Twelve h of Zn2+ treatment was
by itself not able to induce apoptosis in any cell lines (Fig. 2
). On exposure to 1 µM
As2O3 and in the absence of
Zn2+, MT B45 control cells showed a nearly
identical apoptosis rate than with Zn2+ treatment
alone (20% and 19%, respectively). Even without
Zn2+-induced protein expression there was a
pronounced increase in apoptosis in BCR-ABL p210 and P/R9
cells (29% and 40%, respectively) when compared with MT B45 control
cells (19%) and BCR-ABL p185 cells (12%; Fig. 2
). This
effect was most likely due to "leakage" protein expression from the
transgenes, as demonstrated by Western blot (Fig. 1A
). When
cells were treated for 12 h with Zn2+ to
induce protein expression prior to
As2O3 exposure, apoptosis
increased dramatically in the MTp185 and MTp210 populations (77% and
56%, respectively). Taking into account that the
BCR-ABL-positive U937 cells are bulk populations, where only
50–70% of cells express the transgenes (determined by
immunofluorescence studies and further subcloning of the bulk
populations; data not shown), sensitivity of the
p185(BCR-ABL)- and
p210(BCR-ABL)-expressing cells to
As2O3 reached nearly the
same extent than the P/R9 clone (96%).
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Response to As2O3 Is Independent of the
Constitutive ABL Kinase Activity of
BCR-ABL.
BCR-ABL transforms cells via its aberrant constitutive
kinase activity (3)
. To investigate a possible role of
BCR-ABL kinase activity in
As2O3-induced apoptosis, we
exposed BV173 and SD-1 cells to the specific ABL-kinase inhibitor STI
571 [kindly provided by E. Buchdunger (Novartis, Basel,
Switzerland)]. Cells were treated with
As2O3 after a 6-h exposure
to 0.5 µM STI571, to guarantee that
ABL kinase activity was switched off. This is the lowest
possible concentration of STI571, ensuring inhibition of
BCR-ABL kinase activity. In BV173 cells as well as in SD-1
cells STI571 exhibited its known proapototic effects on
BCR-ABL-transformed cells, but had no considerable influence
on response to As2O3. Fig. 3A
shows one of three representative experiments that gave
similar results.
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). In summary, the response to As2O3 in Ph+ lymphoblasts seems to be independent of the constitutive ABL kinase activity of BCR-ABL.
In BCR-ABL-positive Cells
As2O3 Activates Apoptosis without
Caspase-3 Activation or bcl-2 Regulation.
In APL, the role of bcl-2- and caspase-3-like
activity in As2O3-induced
apoptosis is controversially discussed. Reportedly, one of the
mechanisms of decreased susceptibility to apoptosis in
BCR-ABL-positive cells is due to up-regulation of
bcl-2 (12)
. Therefore, we assessed
bcl-2 expression by immunoblotting in BV173 cells on
As2O3 treatment. In
comparison with untreated BV173 cells, no modification of
bcl-2 expression was noted at 8, 24, 48, or 72 h of
As2O3 treatment (Fig. 3B
).
As shown previously, bcl-X expression plays an important
role in protection from various apoptotic stimuli in
BCR-ABL-transfected HL-60 cells (13)
. Two
bcl-X gene products are known:
bcl-XL, an inhibitor of apoptosis, and
bcl-XS, a promoter of apoptosis (reviewed
in Ref. 14
). To answer the question whether variations of
bcl-X isoform expression explains the mechanism of
As2O3-induced apoptosis
in BV173, we probed the above-mentioned immunoblots with an antibody
recognizing bcl-XL as well as
bcl-XS (Santa Cruz Biotechnology). Only
bcl-XL was detected, and no difference in
its expression level between untreated and
As2O3-treated BV173 cells
was seen (Fig. 3B
).
Another key player discussed in the context of
As2O3-induced apoptosis is
caspase-3. (7
, 15)
. Caspases constitute a
family of cysteine proteases with aspartic acid substrate specificity,
thought to be crucial for apoptosis in multicellular organisms
(reviewed in Ref. 14
). To address whether
As2O3-induced apoptosis is
mediated by caspase-3 activity, we probed the same samples
with an antibody specific for PARP (Santa Cruz
Biotechnology), a known substrate for several caspases, including
caspase-3. In presence of activated caspase-3,
PARP is cleaved and the 113 kDa species is replaced
by a 81 kDa species, which is also recognized by the
-PARP antibody. In our experiments, no cleavage of
endogenous PARP was observed after 8, 24, 48, or 72 h
of As2O3 exposure (Fig. 3B
), indicating that caspase-3 is not involved in
As2O3-induced apoptosis of
BCR-ABL-positive BV173 cells.
Taken together, these data give further proof that As2O3 induces apoptosis independent of bcl-2 expression level and caspase-3-like activity.
As2O3 Has No Effect on the CFUs of CD34+
Primary Hematopoietic Precursors.
Clinical studies indicate that APL patients treated with
As2O3 alone do not
experience aplasia of the bone marrow, commonly seen in cytotoxic
chemotherapy regimen (6)
. To assess a possible effect of
As2O3 on normal
hematopoietic progenitor cells, we exposed CD34+ cells isolated from
two patients with Ph+ ALL in CR to 2 µM
As2O3 and tested the CFU in
a methyl-cellulose colony formation assay. The experiments were
performed in triplicates. CD34+ cells were seeded in methyl-cellulose
after 2 days of exposure to
As2O3. There was no
considerable difference regarding number, morphology, composition, or
relationship between GM-CFU, BFU-E, and CFU mix between
the treated and untreated population. A representative depiction of the
growth pattern of the colonies of one of two patients’ samples is
given in Fig. 4
.
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As2O3 Significantly Reduces the CFU of Ph+
Blasts of CML Patients in Blast Crisis.
In BV173 cells a 6-h exposure to
As2O3 is sufficient to
irreversibly induce apoptosis (data not shown). To examine the effect
of As2O3 on primary blasts
of CML patients, we treated PMNCs of five CML patients in myeloid or
lymphatic blast crisis. On
As2O3 exposure there was a
very high variability in viability and total cell number between
different experiments and patient samples, most likely due to the
different sensitivity to culture conditions (data not shown). For that
reason, PMNC samples of two patients, which showed no effect on
As2O3 exposure regarding
total cell number or viability, were seeded in a methyl-cellulose
colony assay (see "Material and Methods"). At the 9th day, the
number of CFUs of the
As2O3-treated samples was
significantly lower than in untreated control cells (Fig. 4
).
Interestingly, on
As2O3-exposure most of the
CFUs exhibited the characteristics of differentiated granulocytic
colonies rather than BFU-E or CFUs (Fig. 4
).
In summary, these data indicate that BCR-ABL increases sensitivity to As2O3-induced apoptosis in Ph+ CML blasts, but not in CD34+ progenitors.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-positive APL, also exhibits potent and
specific activity against BCR-ABL-expressing cells. Without
exception, all Ph+ lymphoblastic cell lines (SD-1, Tom-1, Sup-B15, and
BV173) examined were highly sensitive to
As2O3-induced apoptosis. In
contrast, Ph- cell lines, including the t(4;11)-positive SEM cells,
responded to As2O3-induced
apoptosis. Furthermore, there was no notable difference regarding
response to As2O3 between
the ALL-derived (p185(BCR-ABL) positive) SupB15,
TOM-1, SD-1, and the CMLderived
(p210(BCR-ABL) positive) BV173 cell lines or
between p185(BCR-ABL)- and
p210(BCR-ABL)-transfected U937 cells. Thus, we
conclude that p185(BCR-ABL), as well as
p210(BCR-ABL), is able to mediate response to
As2O3.
Moreover, sensitivity of BCR-ABL-transfected U937 cells to
As2O3-induced apoptosis
also excludes the possibility that the effect of
As2O3 is due to a common
feature of bone marrow cells arrested at the B-cell precursor stage of
differentiation. Instead, it demonstrates that
As2O3-induced apoptosis is
genetically determined by the presence of the t(9;22)-specific chimeric
gene products p185(BCR-ABL) and
p210(BCR-ABL). This effect of BCR-ABL
is analogous to PML/RAR, which determines
As2O3 sensitivity of APL
blasts (6
, 7)
. Other translocation products, such as
HRX-AF4, the product of t(4;11), present in the SEM cells,
did not mediate
As2O3-induced apoptosis.
Initial support for the hypothesis of a genetic determination of the
As2O3 response in Ph+
leukemia was given by the fact that, to the best of our knowledge, only
CML patients were reported to respond to treatment with arsenic
derivatives (1
, 2)
.
Nevertheless, the mechanism by which BCR-ABL mediates As2O3-induced apoptosis remains unclear. As2O3 does not interfere with the constitutive kinase activity of BCR-ABL, and response to As2O3 is not influenced by the abrogation of BCR-ABL kinase activity. Our data indicate that As2O3-induced apoptosis does not interfere with signaling pathways used by BCR-ABL to transform cells. This is, in particular, supported by the fact that the overall tyrosin-phosphorylation pattern of BV173 and SD-1 cells was unaltered in response to As2O3 (data not shown).
All originally BCR-ABL-positive cell lines, as well as
BCR-ABL-transfected U937 cells, have shown clear evidence of
apoptosis after 48–72 h on
As2O3-treatment. As
assessed by immunoblotting, bcl-2 expression was unaffected
by As2O3-treatment up to
72 h. These data confirm recent data on PML/RAR-transfected
U937 and PML/RAR-positive NB4 cells, which underwent apoptosis
without down-regulation of bcl-2 (7
, 16)
. In
our study, we extended the investigation to bcl-X, another
regulator of apoptosis that seems to be influenced by
BCR-ABL (13)
. BV173 expressed high levels of
bcl-XL, but
As2O3-treatment neither led
to down-regulation of bcl-XL nor to
up-regulation of bcl-XS, the proapoptotic
form of bcl-X. PARP cleavage is an important indicator of
caspase activation during apoptosis. Activated caspase-3 is
one of the PARP-cleaving caspases (17)
. We
excluded an involvement of PARP-cleaving caspase
activity in As2O3-treated
BV173 cells. This confirms recent data that showed that PML/RAR is
degraded by PARP-cleaving activity on retinoic acid
treatment, but not by As2O3
(7
, 18)
. Thus, we conclude that in
BCR-ABL-transformed lymphoblasts
As2O3-induced apoptosis is
not mediated by any of the formerly discussed key players, such as
bcl-2, bcl-X or caspase-3-like
activity.
Because we show that the described effects of As2O3 are specific for Ph+ CML blasts, as well as for p185(BCR-ABL)-expressing ALL-derived- and p210(BCR-ABL)-expressing CML-derived cell lines, our data establish As2O3 as a potential agent for the treatment of patients with Ph+ leukemia.
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FOOTNOTES |
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1 Supported by grants from Deutsche
Forschungsgemeinschaft and "Dr. Mildred Scheel–Stiftung" der
Deutschen Krebshilfe e.V. E. P. is a recipient of a fellowship
from the "Deutsche José Carreras Leukämiestiftung e.V."
(DJCLS-99/NAT-1). 
2 To whom requests for reprints should be
addressed, at Med. Klinik III/Abtl. Hämatologie, Klinikum
der J. W. Goethe Universität Frankfurt, Theodor Stern Kai 7,
60590 Frankfurt, Germany. Phone: 49-69-6301-6129; Fax: 49-69-6301-6131;
E-mail: ruthardt{at}em.uni-frankfurt.de
3 The abbreviations used are: CML, chronic
myelogenous leukemia; ALL, acute lymphocytic leukemia; APL, acute
promyelocytic leukemia; FACS, fluorescence-activated cell-sorting;
PARP, poly-(ADP ribose) polymerase; 7-AAD, 7-amino-actinomycin D; CFU,
colony-forming unit; As2O3, arsenic trioxide;
Ph+, Philadelphia chromosome; CR, complete remission; PMNC, peripheral
mononuclear cells; PML/RAR, promyelocytic leukemia gene/retinoic
acid receptor ; GM-CFU, granulocyte-macrophage CFU; BFU-E,
blast-forming unit(s) erythroid.
Received 2/ 4/00. Accepted 5/17/00.
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