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NEOPLASIA
From the Laboratory of Virus Immunology, Institute for
Virus Research, Kyoto University, Kyoto, Japan; Department of Internal
Medicine II and Department of Cell Differentiation, Institute of
Molecular Embryology and Genetics, Kumamoto University School of
Medicine, Japan.
Hypercalcemia is one of the most frequent and serious complications
in patients with adult T-cell leukemia (ATL) and is due to marked bone
resorption by accumulation of osteoclasts (OCLs). Although several
cytokines such as interleukin 1 and parathyroid hormone-related
protein are thought to be involved in the development of high serum
Ca++ levels, its precise underlying mechanism remains
unknown. This study analyzed the expression of various genes that are
thought to regulate serum Ca++ levels in ATL and showed
that the overexpression of the receptor activator of nuclear factor
Adult T-cell leukemia (ATL) is a highly aggressive
neoplastic disease of peripheral helper T lymphocytes that is
etiologically associated with human T-cell leukemia virus type I
(HTLV-I).1-7 There are 4 clinical subtypes of ATL:
smoldering, chronic, lymphoma-type, and acute ATL.8 Of
these subtypes, patients with smoldering and chronic ATL usually have
an indolent clinical course; however, most patients progress to acute
or lymphoma-type ATL several years later. Despite the use of aggressive
chemotherapy, survival of patients with acute or lymphoma-type ATL has
not improved; the mean survival period of patients with acute ATL is
still less than 1 year. The main challenges for a successful treatment
of ATL are drug resistance of ATL cells, high frequency of
opportunistic infections, and hypercalcemia.9
The high frequency of hypercalcemia is the most striking feature
of ATL; about 70% of ATL patients have high serum Ca++
levels during the clinical course of the disease, particularly during
the aggressive stage of ATL.10 Such a frequency is the highest among hematologic malignancies, and hypercalcemia is more severe in patients with ATL than in those with other hematologic malignancies.11 In those patients, serum Ca++
levels are often more than 20 mg/mL, and accordingly, most patients are
in a state of coma.
Several pathologic studies of ATL patients with hypercalcemia
have indicated that high serum Ca++ levels are due to an
increased number of osteoclasts (OCLs) and accelerated bone
resorption.10,12,13 Several cytokines, such as
interleukin-1 (IL-1),14 transforming growth factor
Bone is constitutively remodeled by osteoblasts (the synthesis of
matrix) and OCLs (bone resorption). OCLs are derived from HPCs and
belong to the monocyte macrophage lineage. During differentiation of
OCLs, precursor cells sequentially express c-Fms followed by receptor
activator of nuclear factor In the present study, we demonstrate that ATL cells derived from
patients with hypercalcemia express RANKL messenger RNA and induce the
development of OCLs from HPCs in vitro, indicating that RANKL is
critically involved in the pathogenesis of hypercalcemia in ATL.
Patients
Semiquantitative reverse transcriptase-polymerase
chain reaction
Measurement of serum concentrations of M-CSF, TNF-  were measured by the
sandwich enzyme-linked immunosorbent assay method using Quantikine Human M-CSF immunoassay and Quantikine Human TNF- immunoassay (R&D
Systems, Minneapolis, MN), according to the protocol provided by the
manufacturer. The normal ranges of M-CSF and TNF- were 102 to 765 (n = 30) and less than 15.6 pg/mL, respectively. Serum levels of
PTH-rP were measured by SRL (Tokyo, Japan) using the C-PTH-rP Kit
(Daiichi Radioisotope Lab, Tokyo, Japan). The normal range of serum
PTH-rP was 13.8 to 55.3 pmol/L.
Flow-activated cell sorter analysis and cell sorting Human bone marrow cells were harvested from healthy volunteers and layered onto a Ficoll-Paque (Amersham Pharmacia Biotech, Uppsala, Sweden) gradient and centrifuged for 30 minutes at 400g. Informed consent was obtained from all patients before bone marrow aspiration. After centrifugation, mononuclear cells were collected from the upper layer, and cells were suspended in 5% fetal bovine serum (JRH Bioscience, Lenexa, KS) that contained phosphate-buffered saline (staining buffer) and were incubated with 5 µg/mL mouse immunoglobulin G2a, (antitrinitrophenol) for 30 minutes on ice to block Fc receptors. Subsequently, cells were
incubated with fluorescein isothiocyanate (FITC)-conjugated anti-CD34
antibody (NU4A1) and R-phycoerythrin (R-PE)-conjugated anti-c-Kit
antibody (NU-c-Kit) (both Nichirei, Tokyo, Japan) for 30 minutes on
ice. After 2 washes, cells were suspended with staining buffer,
and cell sorting was performed using a flow-activated cell sorter (FACS) Calibur (Becton Dickinson Immunocytometry Systems, San Jose,
CA). Data were analyzed using Cell Quest software (Becton Dickinson
Immunocytometry Systems).
OCL differentiation in vitro In these experiments, 1 × 103 sorted cells (CD34+c-Kit+ cells) were plated on 96-well culture plates (PRIMARIA; Falcon 3872; Becton Dickinson Labware, Lincoln Park, NJ) and cultured in minimum essential medium
(GIBCO-BRL, Gaithersburg, MD) containing 10% fetal bovine serum with
50 ng/mL recombinant human M-CSF (R&D Systems) alone or together with
25 ng/mL recombinant human RANKL (sRANKL; Peprotech EC, London, United
Kingdom) and 50 U/mL human IL-2 for 7 days. For blocking the effect of
sRANKL, 10 µg/mL recombinant human RANK/Fc or OPG/Fc chimeras (R&D
Systems) was added to the culture, and human sTNF RI (R&D Systems) was
used to block the function of TNF-. In some experiments,
1 × 105 peripheral blood mononuclear cells (PBMCs) from
patients with ATL were added to the culture instead of sRANKL. Cultured
cells were subjected to tartrate-resistant acid phosphatase
(TRAP)-staining or TRAP-solution assay as described
previously.20 To study the osteoclastogenic ability of
PTH-rP, sorted 1 × 103 CD34+
c-Kit+ cells were cultured in -minimum essential medium
containing 10% fetal calf serum with human M-CSF and 10 µg/mL human
PTH-rP 7-34 Amide (Peninsula Lab, San Carlos, CA).
To investigate whether direct interaction between OCL precursor cells and ATL cells is required for OCL formation, a culture insert (0.4 µm; Iwaki Glass, Chiba, Japan) was used. The insert was placed in each well of 24-well culture plates (PRIMARIA, Becton Dickinson), and ATL cells and OCL precursor cells were cultured separated from each other by a membrane filter in the presence of M-CSF and IL-2. In this system, 5 × 103 CD34+c-Kit+ cells were cultured in the bottom with or without 1 × 104 ATL cells on the culture insert. TRAP activity was measured after 7 days of cultivation. Statistical analysis Differences of cytokines between hypercalcemic and normocalcemic patients were examined for statistical significance using the nonparametric Mann-Whitney U test. A P value < .05 denoted the presence of statistically significant difference.
Expression of RANKL messenger RNA in ATL cells An increased number of OCLs in bones, causing bone resorption, is the causative factor of hypercalcemia in ATL. Differentiation of HPCs to OCLs is controlled by several cytokines. Among them, RANKL and M-CSF have been shown to play a major role in the development of OCLs.21 To identify the molecules involved in ATL-associated hypercalcemia, leukemic cells from ATL patients with (8 cases) or without hypercalcemia (7 cases) were studied for the transcriptions and serum levels of various cytokines. The expressions of RANKL, M-CSF, TNF-, and OPG genes was analyzed using
semiquantitative PCR (Figure 1), and
serum levels of M-CSF, TNF-, and PTH-rP were measured (Table 2). As
shown in Figure 1A, the expression of M-CSF gene transcripts varied
among patients with hypercalcemia and those without hypercalcemia
(P = .42, by Mann-Whitney). However, serum levels of M-CSF
were elevated in both groups (Table 2) as reported
previously.26 The level of M-CSF in the sera of HTLV-I
carriers (341.5 ± 24.9) was not different from that of uninfected
individuals (256.8 ± 51.2) (P = .12, by Mann-Whitney), suggesting that ATL cells not present in the peripheral blood were the
source of increased serum M-CSF levels. Thus, serum concentrations of
M-CSF were elevated in patients without hypercalcemia, suggesting that
M-CSF alone is not likely to be responsible for hypercalcemia.
The expression of RANKL gene was higher in ATL cells of patients with hypercalcemia than of those without hypercalcemia and phytohemagglutinin-stimulated PBMCs (Figure 1C; cases 1-7) (P = .012, by Mann-Whitney). However, PTH-rP was elevated in sera of both groups, and its transcription levels were comparable without regard to the presence of hypercalcemia (Figure 1B, Table 2) (P = .20, by Mann-Whitney). For example, PTH-rP was elevated in the serum (253 and 199 pmol/L) and the PTH-rP gene was highly transcribed in leukemic cells of cases 10 and 12, although both patients had normal levels of serum Ca++. In case 8 (with hypercalcemia), serum PTH-rP was elevated (1160 pmol/L), but RANKL expression was not elevated, indicating that markedly increased PTH-rP could cause hypercalcemia. It is possible that elevated PTH-rP induced the expression of RANKL on osteoblasts, resulting in increased OCLs. However, elevated RANKL gene transcription correlated well with hypercalcemia in most hypercalcemic patients. TNF- OPG is the decoy receptor for RANKL,28 which inhibits the function of RANKL and prevents osteoporosis.29 OPG production may abrogate overproduction of RANKL. In our patients, transcription of the OPG gene was observed in ATL cells of cases 3, 4, and 5 (Figure 1E). However, clinical features of these patients were not different from those who did not express OPG. ATL cells from hypercalcemic patients can induce differentiation of OCLs To examine whether ATL cells can induce the differentiation of HPCs to OCLs, PBMCs of ATL patients with or without hypercalcemia were cocultured with CD34+c-Kit+ bone marrow cells along with IL-2 and M-CSF for 7 days. Flow cytometric analysis showed that more than 95% of PBMCs were leukemic cells in these patients. Serum levels of M-CSF were usually elevated in patients with ATL in spite of its transcription in ATL cells (Table 2), suggesting that not only ATL cells but also normal parenchymal cells were responsible for the elevated serum levels of M-CSF. Therefore, we added M-CSF at a concentration of 50 ng/mL, which is compatible to that observed in patients. In addition, fresh ATL cells isolated from the peripheral blood tend to undergo spontaneous apoptosis. Because IL-2 did not cause the proliferation of ATL cells in most cases but inhibited apoptosis of ATL cells, we used this cytokine (50 U/mL) to prevent apoptosis.30 For evaluation of the differentiation and activation of OCLs, TRAP assay was performed. The assay showed positive reaction of TRAP in OCLs but not in macrophages.As a positive control, we used human soluble RANKL and human M-CSF,
which induced differentiation of HPCs into OCLs in vitro (Figure
2). Induction of differentiation of HPCs
into OCLs did not occur when these cells were cultured with M-CSF alone
or with normal CD3+ T cells and M-CSF (Figure 2A, 4 and 5; 2B, 5 and 6). ATL cells of patients with hypercalcemia (cases 1 and 3), but not those of patients without hypercalcemia (cases 10 and
15), induced the differentiation of HPCs into OCLs (Figure 2A,B). The
morphologic features of induced OCLs are shown in Figure
3. Large multinucleated cells were
observed when HPCs were cocultured with ATL cells from cases 1 and 3 (with hypercalcemia). However, such OCLs could not be found when
cocultured with leukemic cells from cases 10 and 15 (without
hypercalcemia).
Inhibition of ATL-induced differentiation of HPCs to OCLs To clarify the mechanism of ATL-induced differentiation of HPCs to OCLs, we used several inhibitors against RANKL and TNF- in coculture
experiments. To block the action of RANKL, we used RANK/Fc and OPG/Fc.
Although both molecules can bind to RANKL, the inhibitory activity of
OPG/Fc is much stronger than that of RANK/Fc. To inhibit the action of
TNF-, we used soluble TNF R1. These inhibitors were added to the
media during coculture of ATL cells and HPCs. As shown in Figure
4A, RANK/Fc failed to suppress ATL-induced differentiation of HPCs to OCLs, and sTNF R1 had no effects
on TRAP assay (data not shown). However, OPG/Fc successfully suppressed
TRAP activities in cases 1 and 3 compared with controls, indicating
that ATL-induced differentiation of HPCs to OCLs was mediated by
interaction between RANKL and RANK (Figure 4B).
Because the soluble forms of RANKL might play a role in the differentiation of OCLs, we examined this possibility by culturing HPCs with ATL cells from patients with hypercalcemia (cases 1 and 3), which were separated by a filter membrane to prevent direct contact (Figure 4A). Inhibition of direct interaction between ATL cells and HPCs resulted in no differentiation into OCLs, suggesting the involvement of cell-bound RANKL and its direct interaction with RANK on HPCs in hypercalcemia.
Mechanism of hypercalcemia in patients with ATL The frequency of hypercalcemia in patients with ATL is markedly high compared with other hematologic malignancies, such as malignant lymphoma (< 10%), acute leukemia (< 1%), and multiple myeloma (20%-40%).11 Its frequency in patients with ATL is reported at about 70% during the whole clinical course, although it tends to be more frequent in those patients with clinically aggressive ATL,10 suggesting that molecules expressed or secreted by ATL cells play an important role in the induction of hypercalcemia. Previous studies have shown an increased number of activated OCLs in the bone of hypercalcemic ATL patients, which resulted in generalized decalcification and hypercalcemia.10 Among several cytokines that are associated with hypercalcemia, PTH-rP has emerged as an important factor in the pathogenesis of high serum Ca++.16 In the present study, case 8, which had high levels of PTH-rP but no increased expression of RANKL, was hypercalcemic, indicating that increased PTH-rP could cause hypercalcemia. Because PTH-rP did not induce the differentiation of HPCs to OCLs in vitro (data not shown), it is possible that increased PTH-rP induced the expression of RANKL on osteoblasts as reported previously31 and indirectly stimulated the differentiation of HPCs into OCLs. However, PTH-rP was also elevated in patients without hypercalcemia, suggesting that elevated PTH-rP alone does not always explain the mechanism of hypercalcemia in most patients with ATL, as reported previously.16,19 However, most patients with hypercalcemia showed increased transcription of RANKL gene, and in vitro coculture experiments demonstrated ATL cell-induced differentiation of HPCs into OCLs. Taken together, increased RANKL expression is thought to be the most important factor in the pathogenesis of ATL-associated hypercalcemia.In this study, coculture of ATL cells with HPCs for 7 days in the presence of IL-2, which might induce the expression of Tax, altered the gene expression. We have previously reported a defective virus that lacked 5'-LTR and internal viral sequences and did not produce Tax because of deletion of the promoter.32 ATL cells in case 1 had this type of HTLV-I provirus, which did not express Tax even after stimulation with phorbol ester (data not shown). This finding proved that Tax expression is not associated with the expression of RANKL gene. Furthermore, we studied the expression of RANKL gene in various HTLV-I-infected cell lines and found that Tax expression did not always correlate with transcription of RANKL gene. In addition, induced expression of Tax in Jurkat cells did not increase the expression of RANKL gene, indicating that Tax expression is not associated with transcription of RANKL gene (our unpublished observation, February 2000). Factors influencing hypercalcemia in ATL patients Our study showed that RANKL on ATL cells plays a critical role in the differentiation of OCLs in patients with ATL, and blocking experiments of direct interaction between ATL cells and HPCs revealed that not a soluble form but a membrane-bound form of RANKL is essential for the differentiation of HPCs to OCLs. In this regard, it is noteworthy that infiltration of ATL cells into the bone marrow was observed in all patients with hypercalcemia in whom bone marrow samples were aspirated (Table 2). Because invasion of ATL cells into the bone marrow is frequently observed during the aggressive stage, it is speculated that certain adhesion molecules expressed on ATL cells enhance such an infiltration process. When such infiltrating ATL cells expressed RANKL on the surface, they induced the differentiation of HPCs to OCLs, resulting in hypercalcemia. Infiltration into the bone marrow by ATL cells without expression RANKL gene did not cause hypercalcemia as observed in case 10 (Table 2). Thus, elevated serum M-CSF levels, expression of RANKL, and ATL infiltration into the bone marrow are critical factors in the pathogenesis of hypercalcemia. PTH-rP secreted from ATL cells might be an additional factor that induces the expression of RANKL on stromal-activated OCLs and exacerbates hypercalcemia.Pathologic role of RANKL Activated T cells regulate bone loss by increased expression of RANKL in inflammatory arthritis.24 Furthermore, in Paget disease,33 increased local expression of RANKL on stromal cells is responsible for accumulation of OCLs in local tissues and subsequent bone resorption, but the expression of RANKL was not sufficient to cause hypercalcemia. However, patients with ATL overexpressed RANKL, which resulted in accumulation of OCLs in the bones in cooperation with M-CSF. It can be explained by several reasons; because ATL is a neoplastic proliferation, RANKL-expressing cells are extremely more abundant than the inflammatory disease.Because ATL cells are derived from activated helper T lymphocytes, secreted cytokines can modify the clinical features. For example, ATL cell-produced IL-5 caused eosinophilia, and granulocyte-monocyte colony-stimulating factor increased the number of neutrophils.34 Monocytosis is one of the clinical features of ATL, in which increased M-CSF should be implicated in the pathogenesis.35 M-CSF increased precursor cells, which supports the differentiation into monocytes and OCLs. Without RANKL, these precursor cells differentiate into monocytes, but once the expression of RANKL is induced in ATL cells, and such leukemic cells infiltrate the bone marrow, these precursor cells differentiate into OCLs. Activated T lymphocytes are known to induce differentiation of cells into OCLs in vitro possibly through RANKL expression.36 In this study, we showed that ATL cells of patients with normal serum Ca++ levels, which exhibit activated phenotypes such as expression of activated antigens like CD25, did not induce differentiation of cells to OCLs. These results clearly show that not the activated phenotype but the expression of RANKL is critical for elevation of serum Ca++ levels. Our study emphasized the significance of RANKL in ATL-associated hypercalcemia. This finding may allow the development of new strategies for the treatment of hypercalcemia and this aggressive disease.
We thank Jun-ichiro Yasunaga and Mika Yoshida for valuable suggestions. We also thank Dr F. G. Issa (word-medex.com.au) for the careful reading and editing of the manuscript.
Submitted April 6, 2001; accepted July 26, 2001.
Supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology in Japan and by grants from Welfide Medicinal Research Foundation and Haraguchi Memorial Cancer Research Fund.
K.N. and T.M. contributed equally to this work.
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: Masao Matsuoka, Laboratory of Virus Immunology, Institute of Virus Research, Kyoto University, Kyoto 606-8507, Japan; e-mail: mmatsuok{at}virus.kyoto-u.ac.jp.
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 A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
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 K. Okuma, K. P. Dalton, L. Buonocore, E. Ramsburg, and J. K. Rose Development of a Novel Surrogate Virus for Human T-Cell Leukemia Virus Type 1: Inhibition of Infection by Osteoprotegerin J. Virol., August 1, 2003; 77(15): 8562 - 8569. [Abstract] [Full Text] [PDF]
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U. Heider, C. Langelotz, C. Jakob, I. Zavrski, C. Fleissner, J. Eucker, K. Possinger, L. C. Hofbauer, and O. Sezer Expression of Receptor Activator of Nuclear Factor {kappa}B Ligand on Bone Marrow Plasma Cells Correlates with Osteolytic Bone Disease in Patients with Multiple Myeloma Clin. Cancer Res., April 1, 2003; 9(4): 1436 - 1440. [Abstract] [Full Text] [PDF]
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O. Sezer, U. Heider, I. Zavrski, C. A. Kuhne, and L. C. Hofbauer RANK ligand and osteoprotegerin in myeloma bone disease Blood, March 15, 2003; 101(6): 2094 - 2098. [Abstract] [Full Text] [PDF]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B ligand on
adult T-cell leukemia cells
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Abstract
Introduction
,
