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NEOPLASIA
From the Division of Hematology, Department of
Medicine, Department of Pathology, Brigham and Women's Hospital,
Harvard Institutes of Medicine, Center for Blood Research, Department
of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston MA; Department of Pathology, Emory University School of
Medicine, Atlanta, GA; and the Howard Hughes Medical Institute, Boston,
MA.
Tyrosine kinase fusion oncogenes that occur as a result of
chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of
autocrine and paracrine expression of hematopoietic cytokines in
leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and
murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD)
caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth
factor beta receptor (PDGF Despite extensive study, the precise role of
hematopoietic cytokines in the development of leukemia is not fully
understood. However, there is evidence to suggest that leukemogenesis
is a cell autonomous process. Murine leukemias induced by the Abelson virus do not require cytokines,1,2 and cytokine messenger RNA (mRNA) levels are not elevated in cultured chronic myelogenous leukemia (CML) cells compared with normal bone marrow
cells.3 Furthermore, BCR/ABL and other
leukemia-associated tyrosine kinase fusions activate
proliferative4 and antiapoptotic pathways5,6 in leukemia cells. Antibody blocking studies have shown that BCR/ABL cell lines do not require granulocyte-macrophage colony-stimulating factor (GM-CSF) to enter the cell cycle,7 nor do they
require interleukin (IL)-3 or GM-CSF to activate downstream cytokine
activation pathways, including the activation of signal transducer and
activator of transcription (STAT) 5.8
However, several lines of evidence suggest that hematopoietic growth
factors might play a critical role in the development of leukemia.
Studies on primary human leukemia cells have shown that they produce
bioactive cytokines9-16 and usually require cytokines for
growth in vitro.17-20 Autocrine production of IL-3 and granulocyte colony-stimulating factor has also been
demonstrated in CD34+ leukemic blasts from some patients
with chronic-phase CML,10 and cytokines may facilitate the
differentiation of CML blasts.21
Also, it is clear that GM-CSF regulates the growth of leukemic cells
from patients with juvenile myelomonocytic leukemia
(JMML).22-25 The central role that GM-CSF plays has
recently been confirmed in a murine model of neurofibromin
(Nf1)-associated JMML.25 However, the relevance of
this finding to other forms of myeloid leukemia is not known.
Data from cell line transfection studies and murine leukemia models
also suggest a role for cytokines in leukemogenesis. BCR/ABL activates
signal transduction pathways that overlap with those activated by
cytokines,26 and hematopoietic cells transfected with
BCR/ABL are growth factor independent27,28 and secrete hematopoietic growth factors.29 Furthermore,
BCR/ABL+ acute lymphoblastic leukemia cell lines produce
GM-CSF and express the GM-CSF receptor,30 and acute
myeloid leukemia (AML) blast cells are responsive to recombinant
GM-CSF.31
Growth factor levels are elevated in several murine models of
leukemia.32-37 Although murine bone marrow transplantation
(mBMT) assays have demonstrated the leukemogenic potential of the
tyrosine kinase fusions BCR/ABL,38 TEL/Janus kinase 2 (JAK2),39 TEL/platelet-derived growth factor beta receptor
(PDGF Furthermore, certain observations in the mBMT experiments have
supported the hypothesis that paracrine stimulation of hematopoietic cells might contribute to the disease phenotype. Zhang and
Ren33 have reported high levels of GM-CSF and IL-3 mRNA
and protein in mice transplanted with bone marrow cells retrovirally
transduced by BCR/ABL.33 In addition, when EGFP is
used as a marker for retroviral infection in mBMT experiments, a
significant proportion of myeloid cells in leukemic mice are
EGFP We sought to conclusively determine the role that the cytokines GM-CSF
and IL-3 play in the development of MPD mediated by tyrosine kinase
fusion proteins. The fusion oncogenes TEL/PDGF Constructs
Mouse strains
Murine bone marrow transplantation Transplant assays were performed as previously described.49 Briefly, donor mice were prepared by a single intraperitoneal dose of 5-fluorouracil (5-FU; 150 mg/kg; Sigma, St Louis, MO) on day 8. Six days later, on day 2, 5-FU-primed mice
were killed, and bone marrow cells were isolated by flushing femurs and
tibias with RPMI media supplemented with 10% fetal bovine serum
(GibcoBRL, Rockville, MD). Cells were incubated at 37°C overnight in
media supplemented with IL-3, stem cell factor, and IL-6 (R&D Systems, Minneapolis, MN). On day 1 the media was changed, 1 mL of retroviral supernatant and 2 µg/µL Polybrene (Sigma) was added, and cells were
centrifuged at 1000g for 90 minutes in a 6-well tissue
culture plate. On day 0, the above centrifuge infection procedure was repeated. Cells were then resuspended in Hanks buffered salt solution (GibcoBRL), at a concentration of 106 cells/mL, and 0.5 to
1.0 mL was intravenously injected into BALB/c mice, lethally irradiated
with 900 cGy by lateral tail vein. Mice were monitored thrice weekly
for the development of disease.
Cytokine quantitation Mice were anesthetized using Metofane (Medical Developments, Springvale, Victoria, Australia), and plasma was obtained by retro-orbital phlebotomy by using heparinized capillary tubes (VWR, McGaw Park, IL). Blood was anticoagulated by using 10 mM EDTA and subjected to centrifugation of 1000g for 5 minutes. Plasma was stored at80°C until analysis. Analysis was performed by using
the commercially available enzyme-linked immunosorbent assay (ELISA;
Cytimmune Sciences, College Park, MD) according to the manufacturer's instructions.
Histopathology and flow cytometry Histopathologic sections were obtained as previously described.40 Spleen cell suspensions were obtained and processed for flow cytometry as described previously.50 In addition, propidium iodide (PI; Sigma) was added to stained and washed cells in some experiments at a final concentration of 100 ng/mL 5 minutes before analysis on the cytometer. Antibodies used in the current analysis were allophycocyanin conjugated anti-Gr-1, phycoerythrin-conjugated anti-Mac-1, biotin-conjugated anti-CD19, and phycoerythrin-conjugated anti-Thy-1.2 (Pharmingen, San Diego, CA). Allophycocyanin-conjugated streptavidin (Caltag, South San Francisco, CA) was used as a secondary reagent to detect biotinylated anti-CD19. Acquisition and data analysis were performed as previously described.40 For high-volume flow cytometry, peripheral blood mononuclear cells were isolated by incubating whole blood from affected animals in red blood cell lysis solution (150 mM NH4Cl, 10 mM KHCO3, 0.1 mM EDTA, pH 7.4) for 5 minutes and washing cells once in phosphate-buffered saline. Unstained cells were then analyzed for EGFP fluorescence, using a MoFlo flow cytometer and CyCLOPS Summit software (Cytomation, Fort Collins, CO).
Cytokine levels are elevated in mice by leukemia-associated tyrosine kinase fusion proteins Murine BMT experiments using wild-type Balb/c donor and recipient mice and TEL/JAK2, TEL/PDGF R, and TEL/TRKC were performed. As has
been described previously, 100% of mice developed MPD (data not
shown). At 3 to 5 weeks following transplant, plasma samples from
Balb/c mice transplanted with nontransduced marrow (n = 3) and mice
transplanted with vector-transduced marrow (n = 6), TEL/PDGFR (n = 6), TEL/TRKC (n = 3), or TEL/JAK2 (n = 3) were analyzed for the cytokines GM-CSF and IL-3 by the ELISA immune assay (Figure 1). In related studies,51 we
found that mice with BCR/ABL-induced MPD had increased IL-3 levels but
normal levels of GM-CSF. The mean levels of IL-3 were significantly
elevated in mice transplanted with TEL/PDGFR (14-fold) and TEL/JAK2
(11-fold) compared to control mice. Levels of IL-3 were also elevated
in TEL/TRKC mice (4.5-fold) but did not achieve statistical
significance.
The same samples were also quantitatively assayed for GM-CSF (Figure
1). Like BCR/ABL, transplantation with TEL/TRKC did not substantially
elevate GM-CSF levels. The mean GM-CSF level in mice transplanted with
TEL/JAK2 was elevated (34%) but not significantly (Figure 1). In
contrast, TEL/PDGF Tyrosine kinase fusions cause fatal myeloproliferation in mice deficient for GM-CSF and IL-3 To directly determine the role of GM-CSF and IL-3 in the development of tyrosine kinase-induced MPD, mBMT experiments were performed using bone marrow derived from mice genetically deficient in both GM-CSF and IL-3 (double knockout mice) (Gillessen et al, manuscript submitted). Mice transplanted with TEL/PDGFR, TEL/JAK2, or with TEL/TRKC (Table 1) all (100%)
developed fatal MPD with the same latency as seen in experiments with
wild-type donors (Table 1 and data not shown). To exclude the
possibility that GM-CSF or IL-3 secreted from recipient stromal cells,
residual hematopoietic cells, or other tissue sources contributed to
leukemogenesis, we repeated a set of transplant experiments by using
mice deficient in GM-CSF and IL-3 both as bone marrow donors and as
transplant recipients. All of these mice also developed MPD (Table 1
and Figure 2). The results described
below refer to data obtained from mice transplanted using GM-CSF/IL-3
deficient marrow into GM-CSF/IL-3 deficient recipients.
The latency of disease in TEL/JAK2 and TEL/PDGF Flow cytometric analysis of cells isolated from the spleens of affected
animals demonstrated an abnormal population of Gr-1+,
Mac-1+ mature granulocytes (Figure
3). These results are similar to those
obtained previously in mBMTs with wild-type marrow and wild-type recipients.39-41 These data indicate that mice that are
genetically deficient in GM-CSF and IL-3 develop fatal MPD in response
to TEL/PDGF
A large proportion of EGFP R40 with the IRES-EGFP vector are
EGFP , and it was suggested that this represented
paracrine stimulation of nontransduced myeloid cells by IL-3 and/or
GM-CSF.33 However, we found a similar population of
GR-1+/EGFP myeloid cells in mice transplanted
with TEL/PDGFR or TEL/TRKC when both donor and recipient were
IL-3/GM-CSF double knockout mice (Figure
4A). To further assess potential
paracrine contributions to disease, we performed propidium iodide (PI)
staining to assess viability of EGFP+ and
EGFP myeloid lineage cells in leukemic mice. We found
that in mice transplanted with TEL/PDGFR or TEL/TRKC, 46% to 78%
of Gr-1+/EGFP cells did not exclude PI,
indicating that they were not viable (Figure 4B). In contrast, only 1%
to 2% of Gr-1+/EGFP+ cells were PI positive,
indicating that nearly all of the EGFP+ cells were viable
at the time of analysis. A similar effect was seen in the
TEL/JAK2-transplanted mice (data not shown). PI gating to exclude
nonviable cells thus substantially decreased the population of
EGFP cells and correspondingly decreased the magnitude of
the putative paracrine effect as manifested by EGFP
cells. To further assess this phenomenon, fresh peripheral blood cells
from 2 animals with TEL/PDGFR-induced MPD were analyzed for EGFP
expression without subjecting the cells to the prolonged antibody
incubation necessary for immunophenotype analysis. EGFP
cells comprised only 5% to 8% of total cells analyzed in this fashion
(Figure 4A). Taken together, these data indicated that the
EGFP cell population was not the consequence of paracrine
stimulation of nontransduced marrow. Rather, these data suggest that a
significant proportion of the EGFP myeloid cells are
nonviable and that the time and/or washing steps required for
processing cells for immunophenotype analysis increases the number of
EGFP myeloid cells.
Direct assessment of paracrine stimulation of bone marrow cells in mixing experiments Although PI gating decreased the magnitude of the EGFP cell population, there was still a significant
proportion of Gr-1+/EGFP cells present in MPD
spleens (10% to 18%). To more directly assess a paracrine
contribution to the disease phenotype, we performed experiments in
which bone marrow cells transduced with TEL/PDGFR retrovirus lacking
EGFP were admixed with bone marrow cells transduced with a retrovirus
containing EGFP but no tyrosine kinase fusion oncogenes (Figure
5A). A significant paracrine contribution
to the leukemia phenotype would be expected to result in expansion of
the EGFP+ population of cells. As a positive control for a
paracrine effect, bone marrow cells transduced with a retrovirus
containing GM-CSF were also admixed with EGFP-transduced bone marrow
cells. In MPD induced by retroviral transduction of GM-CSF, a
significant proportion of cells in the spleen of disease animals are
Gr-1+/EGFP+ (15%), consistent with
GM-CSF-mediated paracrine stimulation of cells. In contrast, when
TEL/PDGFR-transduced cells were admixed with EGFP-expressing cells,
only 2% of the Gr-1+ population was EGFP+
(Figure 5B). These data indicated that the MDP induced by TEL/PDGFR did not rely to any significant extent on paracrine
mechanisms.
Recent findings have suggested that cell nonautonomous factors,
such as hematopoietic cytokines, might contribute to disease pathogenesis in human MPD and in mBMT models of MPD induced by tyrosine
kinase fusions.33 Indeed, we have observed elevated IL-3
protein levels in the plasma of mice with MPD induced by all of the
tyrosine kinase fusions examined. Elevations in levels of GM-CSF were
more modest. We have demonstrated that GM-CSF and IL-3 are not required
for development of MPD induced by BCR/ABL.51 Furthermore,
in the experiments described above, we have shown that TEL/PDGF To definitively test the role of both IL-3 and GM-CSF in the development of disease in mice, we used a strategy whereby the respective tyrosine kinase fusion protein associated with human leukemia is retrovirally transduced into bone marrow that is deficient for GM-CSF and IL-3. We observed no significant differences in histopathology, immunophenotype, or disease latency when comparing GM-CSF/IL-3 double-deficient hematopoietic progenitors with wild-type progenitors. Furthermore, there were also no differences in the histopathology or immunophenotype when double-deficient mice were used both as marrow donors and as recipients, eliminating the possibility that stromal cells elaborate GM-CSF or IL-3 necessary for disease pathogenesis. These data demonstrate that these cytokines are not required for development of disease in this model. Although all animals eventually succumbed to disease, when IL-3- and GM-CSF-deficient cells expressing TEL/TRKC were transplanted into doubly deficient recipient mice, 2 of 4 animals survived longer than expected. This phenomenon was not seen when deficient donor cells were transplanted into wild-type recipients. Although we cannot exclude the possibility that there is a subtle effect on disease latency in TEL/TRKC mice, the fact that the other mice in this experiment died rapidly from MPD suggests that there may be a recipient-related effect on survival besides the development of disease per se. For example, the accumulation in the lungs of surfactant lipids reported in GM-CSF-deficient mice52-54 may have protected these mice from death due to pulmonary infiltration and/or hemorrhage. This hypothesis is consistent with data indicating that TEL/TRKC activates signal transduction pathways distinct from those activated by the other tyrosine kinase fusions tested.41 In mice transplanted with hematopoietic progenitors transduced with
TEL/JAK2, TEL/PDGF However, not all of the EGFP The lack of evidence for a contribution of GM-CSF and IL-3 to the
disease phenotype in the murine model of leukemia should be interpreted
with caution. We have excluded a central role for GM-CSF and IL-3 in
disease pathogenesis induced by each of the tyrosine kinase fusion
oncogenes tested in our model, and we find no evidence for paracrine
stimulation in the case of TEL/PDGF In summary, analysis of mice deficient in GM-CSF and IL-3 has demonstrated that these cytokines are not required in an mBMT assay for the development of MPD induced by a spectrum of tyrosine kinase fusions associated with human hematologic malignancy.
We thank Francesca Garcia for secretarial assistance, and Dr Katherine Weilbaecher and Dr Timothy Ley for critical reading of the manuscript. G.D. is a Clinical Scholar of the Leukemia and Lymphoma Society. R.A.V.E. is a Scholar of the Leukemia and Lymphoma Society and the Carl and Margaret Walter Scholar in Blood Research at Harvard Medical School.
Submitted July 20, 2000; accepted November 20, 2000.
Supported in part by National Institute Health grants CA81197-01 (M.H.T.), AR44628 (I.R.W.), CA57593 (R.A.V.E.), CA74886, CA39542 (G.D.), DK50654, and CA66996 (D.G.G.) and the MarJo Foundation. Support was also received from the Swiss National Science Foundation, the Swiss Cancer League (S.G.), and the Cancer Research Institute/Partridge Foundation (G.D.).
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: Michael H. Tomasson, Division of Oncology Services, Section of Bone Marrow Transplantation, 660 South Euclid Ave, Campus Box 8007, St Louis, MO 63110.
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TEL/PDGF |
Top
Abstract
Introduction
