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Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4747-4751
Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID
Mice Engrafted With Adult T-Cell Leukemia Cells
By
Akifumi Takaori-Kondo,
Kazunori Imada,
Itsuo Yamamoto,
Akane Kunitomi,
Yasuharu Numata,
Hitoshi Sawada, and
Takashi Uchiyama
From the Institute for Virus Research, Kyoto University, Sakyo-ku,
Kyoto, Japan; the Department of Radiology, Shiga University of Medical
Sciences, Otsu, Shiga, Japan; and the Department of Internal Medicine,
Kokura Memorial Hospital, Kokurakita-ku, Kita-kyusyu, Japan.
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ABSTRACT |
Parathyroid hormone-related protein (PTHrP) is considered to be one
of the main causes of hypercalcemia associated with adult T-cell
leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the
development of hypercalcemia in ATL, we examined the SCID mouse model
of ATL that has previously been shown to mimic the disease in humans.
Using this model, we found clear elevations in serum levels of calcium
and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL
cells proliferating in vivo. After the development of hypercalcemia,
ATL mice were killed and bone histomorphometric analysis was performed.
Bone volume was clearly decreased in the ATL mice. In comparison to
control SCID mice, bone formation indices were very low in the ATL
mice. Surprisingly, no significant difference was detected between the
ATL mice and the control SCID mice in eroded surface/bone surface
(ES/BS), a parameter of bone resorption. To our knowledge, the model
presented here is the first animal model of ATL with humoral
hypercalcemia. This is in contrast to previously reported,
well-characterized animal models of human solid tumors associated with
humoral hypercalcemia of malignancy (HHM). Furthermore, this model not
only provides us with the opportunity to study the mechanisms
underlying development of elevated calcium levels in ATL, but also
allows us to test new therapeutic agents designed to treat
hypercalcemia.
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INTRODUCTION |
ADULT T-CELL LEUKEMIA (ATL) is caused by
infection with human T-cell leukemia virus type-I (HTLV-I) and is
associated with characteristic clinical features.1-4
Hypercalcemia is frequently associated with ATL and contributes
significantly to mortality in this disease.5 Parathyroid
hormone-related protein (PTHrP) is considered to be one of the primary
causes of hypercalcemia associated with ATL.6,7 PTHrP was
originally identified as a factor produced by tumors with humoral
hypercalcemia of malignancy (HHM)8-10 and is overexpressed
by a variety of tumors.11 PTHrP is expressed in normal
tissues12 and plays a wide range of physiological roles.
ATL cells have been shown to produce PTHrP. HTLV-I Tax transactivates
the PTHrP gene promoter,7 and interleukin-2 (IL-2) induces
the production of PTHrP in ATL cells.13,14 However, we have
found previously that IL-2 mRNA is not detected in peripheral blood
leukemic cells from ATL patients.15 In addition, HTLV-I viral expression is usually undetectable or at very low levels in fresh
ATL cells.16,17 Therefore, the mechanism by which the PTHrP
gene is overexpressed in ATL cells remains unclear. Furthermore, due to
the absence of an appropriate animal model, the role of PTHrP in the
development of hypercalcemia in ATL in vivo has not been well
characterized.
We have previously developed an in vivo proliferative model of ATL
using severe combined immunodeficient (SCID) mice to study the
mechanism of neoplastic cell growth of ATL in vivo.18-20 We found that the microenvironment provided by SCID mice was more suitable
for leukemic cell growth than the conditions provided by in vitro cell
culture. We have also recently developed a serial transplantation model
of ATL cells in SCID mice, which closely resembles the disease in
humans.21 Use of this model to study the function and
regulation of PTHrP should provide additional information concerning
the development of hypercalcemia in ATL.
In this study, we show that the serial transplantation model of ATL
presents with hypercalcemia associated with marked elevations in serum
C-PTHrP levels. We further characterize changes in bone metabolism seen
in this model.
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MATERIALS AND METHODS |
Mice.
Immune-deficient SCID (CB17scid/scid) mice were obtained from Nihon
Clea Inc (Tokyo, Japan). The mice were bred and maintained under
specific pathogen-free conditions in the animal facility of the
Institute for Virus Research, Kyoto University (Kyoto, Japan). Age-matched SCID mice were used as controls in all
experiments.
Injection of ATL cells into SCID mice.
ATL cells were serially transplanted into SCID mice as previously
described.21 In brief, lymph node cells (LNC) from a
lymphoma-type ATL patient were injected intraperitoneally into SCID
mice. Tumor cells were recovered from the mice engrafted with ATL cells
and were serially transplanted into SCID mice.
Measurement of serum levels of calcium and C-terminal PTHrP
(C-PTHrP).
Calcium and C-PTHrP levels were measured using blood obtained from the
hearts of mice that had been killed. Serum calcium levels were
determined by an o-cresol-phthalein complexone method using a
Calcium-C-Test Wako kit (Wako, Osaka, Japan) according to the
manufacturer's instruction. Serum C-PTHrP levels were determined by
radioimmunoassay specific for the C-terminal region (109-141) of human
PTHrP using a C-PTHrP RIA kit (Daiichi Isotope Co Ltd, Tokyo, Japan).
Reverse transcription-polymerase chain reaction (RT-PCR).
Single-strand cDNA was synthesized in a volume of 20 µL, as
previously described.20 The cDNA preparation was then
diluted to 100 µL. cDNA (2.5 µL) was amplified in a volume of 25 µL in the presence of 800 nmol/L 5 and 3 primers, 200 µmol/L dNTPs, 1 U Taq polymerase (TAKARA, Otsu, Japan), and 2.5 mmol/L MgCl2. The PCR primers specific for PTHrP were used
as previously described.22 PTHrP amplification was
performed in a thermal cycler (Perkin Elmer Cetus, Norwalk, CT) for 38 cycles. The cycling conditions were 1 minute at 94°C for
denaturation, 1 minute at 67°C for annealing, and 2 minutes at
72°C for elongation.  -Actin amplification was performed using
the human-specific primers as previously described.20 The
amplified products were then visualized after electrophoresis through
1.5% agarose gels by staining with ethidium bromide.
Bone histomorphometric analysis.
Mice were subcutaneously injected with calcein (10 mg/kg) and
tetracyclin (20 mg/kg) at an interval of 7 days. Lumbar vertebrae obtained from mice that had been killed were fixed in 70% ethanol. Fixed bone specimens were stained with the Villanueva bone stain and
then embedded in methyl methacrylate. Bone histomorphometric analysis
using dry thin sections was performed with Osteoplan (Karl-Zeiss,
Oberkochen, Germany). Statistical analysis was performed using the Student's t-test. The criterion of significance
was P < .01. All values were reported as the mean ± standard deviation (SD). Wet thin sections were further stained with
the Villanueva Goldner stain.
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RESULTS |
Mice engrafted with ATL cells.
As we have previously reported,21 mice engrafted with ATL
cells developed disease closely resembling that of the original patient. Proliferating tumor cells obtained from the engrafted mice
that were shown to be from the same clone as the original leukemic
cells did not express either HTLV-I or IL-2 mRNA. No changes were noted
in these characteristics during serial transplantations. In the present
study, mice were analyzed at 12 to 14 passages. All the mice exhibited
lethargy, ruffled fur, and a hunched posture and were found to have
tumors within 3 weeks after inoculation of tumor cells.
Serum levels of calcium and C-PTHrP.
As shown in Table 1, both serum calcium
levels and serum C-PTHrP levels were markedly elevated in SCID mice
engrafted with ATL cells, as compared with the age-matched control SCID
mice. Unfortunately, we were unable to measure serum vitamin D levels due to insufficient serum volume.
Expression of PTHrP mRNA.
We next performed RT-PCR analysis to determine whether the tumor cells
proliferating in vivo expressed PTHrP mRNA. RT-PCR analysis showed that
the tumor cells expressed PTHrP mRNA at greater levels than MT-2, an
HTLV-I-infected cell line,23 that has previously been
shown to secrete PTHrP24 (Fig
1). A strong signal for PTHrP mRNA was detected in both the original
ATL cells as well as tumor cells obtained from the ATL mice.
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| Fig 1.
Expression of PTHrP mRNA by RT-PCR analysis in the
original leukemic cells and tumor cells from ATL mice. To detect
-actin and PTHrP mRNAs, PCR was performed for 25 and 38 cycles,
respectively. C, negative control (RT reaction without RNA).  X174
DNA digested with HinfI was used as a molecular weight marker
(M).
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Bone histomorphometric analysis.
To study bone remodeling in this model, bone histomorphometric analysis
was performed (Table 2). Bone volume/tissue
volume (BV/TV) was clearly decreased in the mice engrafted with ATL
cells (P = .0077). Indicators of bone formation, such as
osteoid volume/bone volume (OV/BV), osteoid surface/bone surface
(OS/BS), and bone formation rate/bone volume (BFR/BV), were markedly
decreased in the ATL mice compared with those in the age-matched
control SCID mice (P = .0011, .0023, and .0087, respectively).
A marked decrease in osteoid surface in an ATL mouse compared with a
control SCID mouse is shown in Fig 2. In
contrast to these findings, no significant difference was detected
between the ATL mice and the control mice in eroded surface/bone
surface (ES/BS), a parameter of bone resorption.
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| Fig 2.
Villanueva Goldner staining of representative sections of
lumbar vertebra from a control mouse and an ATL mouse. Arrows indicate osteoid surface, which is markedly decreased in an ATL mouse (A) compared with a control SCID mouse (B).
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DISCUSSION |
In the present study, we characterize a unique SCID mouse model of ATL
that develops hypercalcemia, most likely through excess production of
PTHrP by ATL cells proliferating in vivo. To our knowledge, this is the
first animal model of ATL with hypercalcemia. Hypercalcemia is a
frequent and fatal complication of ATL.5 In solid tumors,
PTHrP has been shown to have a causative role in the development of
hypercalcemia in studies using patient samples and animal models of
HHM.25-27 PTHrP is also considered to be a causative factor
of ATL-associated hypercalcemia,6,7 although other humoral
factors such as IL-1 and transforming growth factor- have been reported to be involved.28,29 Most of the studies on the function and regulation of PTHrP in ATL have been in vitro experiments, because no appropriate animal model has been available. Furthermore, most of the HTLV-I-infected cell lines used in these studies are derived from nonleukemic cell clones, which have properties quite different from those of leukemic cells.20,30
Therefore, the precise mechanisms underlying the development of
hypercalcemia in ATL as well as the function of PTHrP and the
regulation of its expression in ATL remain to be determined. To help
answer these questions, an appropriate animal model is needed.
The SCID mouse model of ATL-associated hypercalcemia presented in this
study provides us with insights into the development of hypercalcemia
in vivo. Mice engrafted with leukemic cells from an ATL patient who
developed hypercalcemia in the terminal stage of the disease showed
moderately high levels of serum C-PTHrP and calcium. In addition, PTHrP
mRNA was detected both in the original leukemic cells and tumor cells
proliferating in the ATL mice. Collectively, these data strongly
suggest that PTHrP is one of the main causes of hypercalcemia in this
model as well as in the original patient.
Bone histomorphometric analysis of this model showed that indices of
bone formation were clearly lower in the ATL mice than in the
age-matched control SCID mice. Surprisingly, ES/BS, an indicator of
bone resorption, was normal in the ATL mice as compared with the
control SCID mice. In addition, no significant difference was found in
the number of osteoclasts in these two groups of mice (data not shown).
A characteristic feature associated with PTHrP secretion found in
patients with HHM is uncoupling, the process of excessive bone
resorption with suppressed bone formation.11,31 To date,
there has been no report on in vivo bone remodeling in ATL patients. In
light of these data, another factor(s) produced by ATL cells may
modulate the bone changes induced by PTHrP in this model.
Tax of HTLV-I and IL-2 have been reported to upregulate PTHrP gene
expression.7,13,14 Tax transactivates the PTHrP gene through interaction with cellular transcription factors such as AP1,
AP-2, Ets1, and Sp1.32-34 However, neither HTLV-I nor IL-2 mRNA was detectable in the tumor cells proliferating in
vivo.20,21 The interaction between leukemic cells and the
microenvironment provided by SCID mice may play an important role in
the overexpression of the PTHrP gene in ATL cells proliferating in
vivo. Wake et al35 have reported that PTHrP gene expression
is induced via the leukocyte function-associated antigen-1
(LFA-1)/intracellular adhesion molecule-1 (ICAM-1) pathway in vitro. We
have found that LFA-1 molecules are expressed on the tumor cells
proliferating in the ATL mice (data not shown). However, as we reported
previously, the LFA-1/ICAM-1 pathway is not functional in vivo as
adhesion molecules, although LFA-1 molecules are expressed on fresh
leukemic cells from ATL patients.36 It would be of interest
to identify the factors or mechanisms that induce PTHrP gene expression
in vivo using this model. Recently, it has been shown that PTHrP gene
expression is affected by p53.37,38 Point mutation of the
p53 gene has been found in a considerable proportion of ATL cases.39,40 Such a genetic change might be responsible for enhanced expression of the PTHrP gene, leading to the development of
hypercalcemia in ATL.
It is still controversial whether PTHrP has any effect on ATL cell
growth. McCauley et al41 reported that MT-2 cells have receptors for PTHrP and that PTHrP inhibits MT-2 cell growth. Inoue et
al42 reported that 22-oxacalcitriol suppresses both cell
proliferation and PTHrP gene expression in MT-2 cells. However, these
data must be carefully interpreted, because MT-2 is a cell line
transformed by the infection of HTLV-I in vitro. Our model will enable
us to examine the effect of PTHrP on ATL cell growth in vivo.
Finally, hypercalcemia is one of the main causes of death in ATL. This
model will be very useful not only for clarifying the in vivo role of
PTHrP and bone remodeling in ATL, but also for developing novel
therapeutic strategies to treat hypercalcemia and improve the prognosis
of patients with this disease.
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FOOTNOTES |
Submitted February 19, 1997;
accepted February 17, 1998.
Supported in part by grants from the Ministry of Education, Science,
Sport, and Culture, Japan, and Sankyo Foundation of Life Science.
Address reprint requests to Takashi Uchiyama, MD, Institute for Virus
Research, Kyoto University, 53 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606, Japan.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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REFERENCES |
1.
Uchiyama T,
Yodoi J,
Sagawa K,
Takatsuki K,
Uchino H:
Adult T-cell leukemia: Clinical and hematological features of 16 cases.
Blood
50:481,
1977[Free Full Text]
2.
Yodoi J:
Adult T cell leukemia in Japan
, in Seno S,
Takaku F,
Irino S
(eds):
Topics in Hematology.
Amsterdam, The Netherlands, Excerpta Medica
, 1977
, p 73
3.
Poiesz BJ,
Ruscetti FW,
Gazdar AF,
Bunn PA,
Minna JD,
Gallo RC:
Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.
Proc Natl Acad Sci USA
77:7415,
1980[Abstract/Free Full Text]
4.
Hinuma Y,
Nagata K,
Hanaoka M,
Nakai M,
Matsumoto T,
Kinoshita K-I,
Shirakawa S,
Miyoshi I:
Adult T-cell leukemia: Antigen in an ATL cell line and detection of antibodies to the antigen in human sera.
Proc Natl Acad Sci USA
78:6476,
1981[Abstract/Free Full Text]
5.
Bunn PA Jr,
Schechter GP,
Jaffe E,
Blayney D,
Young RC,
Matthews MJ,
Blattner W,
Broder S,
Robert-Guroff M,
Gallo RC:
Clinical course of retrovirus-associated adult T-cell lymphoma in the United States.
N Engl J Med
309:257,
1983[Abstract]
6.
Motokura T,
Fukumoto S,
Matsumoto T,
Takahashi S,
Fujita A,
Yamashita T,
Igarashi T,
Ogata E:
Parathyroid hormone-related protein in adult T-cell leukemia-lymphoma.
Ann Intern Med
111:484,
1989
7.
Watanabe T,
Yamaguchi K,
Takatsuki K,
Osame M,
Yoshida M:
Constitutive expression of parathyroid hormone-related protein gene in human T-cell leukemia virus type I (HTLV-I) carriers and adult T-cell leukemia that can be transactivated by HTLV-I tax gene.
J Exp Med
172:759,
1991[Abstract/Free Full Text]
8.
Suva LJ,
Winslow GA,
Wettenhall R,
Hammonds RG,
Moseley JM,
Diefenbach-Jagger H,
Rodda CP,
Kemp BE,
Rodriguez H,
Chen EY,
Hudson PJ,
Martin TJ,
Wood WI:
A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression.
Science
237:893,
1987[Abstract/Free Full Text]
9.
Burtis WJ,
Wu T,
Bunch C,
Wysolmerski JJ,
Insogna KL,
Weir EC,
Broadus AE,
Stewart AF:
Identification of a novel 17,000-dalton parathyroid hormone-like adenylatecyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy.
J Biol Chem
262:7151,
1987[Abstract/Free Full Text]
10.
Strewler GJ,
Stern PH,
Jacobs JW,
Eveloff J,
Klein RF,
Leung SC,
Rosenblatt M,
Nissenson RA:
Parathyroid hormone like protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone.
J Clin Invest
80:1803,
1987
11.
Broadus AE,
Mangin M,
Ikeda K,
Insogna KL,
Weir EC,
Burtis WJ,
Stewart AF:
Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide.
N Engl J Med
319:556,
1988[Medline]
[Order article via Infotrieve]
12.
Martin TJ,
Moseley JM,
Gillespie MT:
Parathyroid hormone-related protein: Biochemistry and molecular biology.
Crit Rev Biochem Mol Biol
26:377,
1991[Medline]
[Order article via Infotrieve]
13. .
Mori N,
Ohsumi K,
Murakami S,
Wake A,
Shirakawa F,
Morimoto I,
Oda S,
Eto S:
Enhancing effect of interleukin-2 on production of parathyroid hormone-related protein by T-cell leukemia cells.
Jpn J Cancer Res
84:425,
1993[Medline]
[Order article via Infotrieve]
14. .
Ikeda K,
Okazaki R,
Inoue D,
Ohno H,
Ogata E,
Matsumoto T:
Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: Possible role in hypercalcemia associated with adult T cell leukemia.
Endocrinology
132:2551,
1993[Abstract/Free Full Text]
15.
Kodaka T,
Uchiyama T,
Umadome H,
Uchino H:
Expression of cytokine mRNA in leukemic cells from adult T cell leukemia patients.
Jpn J Cancer Res
80:531,
1989[Medline]
[Order article via Infotrieve]
16.
Franchini G,
Wong-Staal F,
Gallo RC:
Human T-cell leukemia virus (HTLV-I) transcripts in fresh and cultured cells of patients with adult T-cell leukemia.
Proc Natl Acad Sci USA
81:6207,
1984[Abstract/Free Full Text]
17.
Kinoshita T,
Shimoyama M,
Tobinai K,
Ito M,
Ito S-I,
Ikeda S,
Tajima K,
Shimotohno K,
Sugimura T:
Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction.
Proc Natl Acad Sci USA
86:5620,
1989[Abstract/Free Full Text]
18.
Kondo A,
Imada K,
Hattori T,
Yamabe H,
Tanaka T,
Miyasaka M,
Okuma M,
Uchiyama T:
A model of in vivo cell proliferation of adult T-cell leukemia.
Blood
82:2501,
1993[Abstract/Free Full Text]
19.
Takaori-Kondo A,
Hosono M,
Imada K,
Yao ZS,
Sakahara H,
Yamabe H,
Konishi J,
Okuma M,
Uchiyama T:
Detection of homing, proliferation, and infiltration sites of adult T cell leukemia cells in severe combined immunodeficiency mice using radiometric techniques.
Jpn J Cancer Res
86:322,
1995[Medline]
[Order article via Infotrieve]
20.
Imada K,
Takaori-Kondo A,
Akagi T,
Shimotohno K,
Sugamura K,
Hattori T,
Yamabe H,
Okuma M,
Uchiyama T:
Tumorigenicity of human T-cell leukemia virus type I-infected cell line in severe combined immunodeficient mice and characterization of the cells proliferating in vivo.
Blood
86:2350,
1995[Abstract/Free Full Text]
21.
Imada K,
Takaori-Kondo A,
Sawada H,
Imura A,
Kawamata S,
Okuma M,
Uchiyama T:
Serial transplantation of adult T cell leukemia cells into severe combined immunodeficient mice.
Jpn J Cancer Res
87:887,
1996[Medline]
[Order article via Infotrieve]
22.
Walsh CA,
Birch MA,
Fraser WD,
Robinson J,
Lawton R,
Dorgan J,
Klenerman L,
Gallagher JA:
Primary cultures of human bone-derived cells produce parathyroid hormone-related protein: A study of 40 patients of varying age and pathology.
Bone Miner
27:43,
1994[Medline]
[Order article via Infotrieve]
23.
Miyoshi I,
Kubonishi I,
Yoshimoto S,
Akagi T,
Ohtsuki Y,
Shiraishi Y,
Nagata K,
Hinuma Y:
Type C virus particles in a cord T-cell line derived by co cultivating normal human cord leukocytes and human leukaemic T cells.
Nature
294:770,
1981[Medline]
[Order article via Infotrieve]
24.
Fukumoto S,
Matsumoto T,
Watanabe T,
Takahashi H,
Miyoshi I,
Ogata E:
Secretion of parathyroid hormone-like activity from human T-cell lymphotropic virus type I-infected lymphocytes.
Cancer Res
49:3849,
1989[Abstract/Free Full Text]
25.
Ikeda K,
Matsumoto T,
Fukumoto S,
Kurokawa K,
Ueyama Y,
Fujishige K,
Tamaoki N,
Saito T,
Ohtake K,
Ogata E:
A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy.
Calcif Tissue Int
43:97,
1988[Medline]
[Order article via Infotrieve]
26.
Miyake Y,
Yamaguchi K,
Honda S,
Nagasaki K,
Tsuchihashi T,
Mori M,
Kimura S,
Abe K:
Production of parathyroid hormone-related protein in tumor xenografts in nude mice presenting with hypercalcemia.
Br J Cancer
63:252,
1991[Medline]
[Order article via Infotrieve]
27.
Schilling T,
Blind E,
Baier R,
Sinn HP,
Moallem E,
Silver J,
Ziegler R,
Raue F:
Effects of passive immunization against parathyroid hormone-related protein: PTHrP is the responsible factor in mediating hypercalcemia in the Walker carcinosarcoma 256 rat model.
J Bone Miner Res
10:7,
1995[Medline]
[Order article via Infotrieve]
28.
Wano Y,
Hattori T,
Matsuoka M,
Takatsuki K,
Chua AO,
Gubler U,
Greene WC:
Interleukin 1 gene expression in adult T cell leukemia.
J Clin Invest
80:911,
1987
29.
Niitsu Y,
Urushizaki Y,
Koshida Y,
Terui K,
Mahara K,
Kohgo Y,
Urushizaki I:
Expression of TGF- gene in adult T cell leukemia.
Blood
71:263,
1988[Abstract/Free Full Text]
30.
Maeda M,
Shimizu A,
Ikuta K,
Okamoto H,
Kashihara M,
Uchiyama T,
Honjo T,
Yodoi J:
Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia.
J Exp Med
162:2169,
1985[Abstract/Free Full Text]
31.
Stewart AF,
Vignery A,
Silverglate A,
Ravin ND,
LiVolsi V,
Broadus AE,
Baron R:
Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: Uncoupling of bone cell activity.
J Clin Endocrinol Metab
55:219,
1982[Abstract/Free Full Text]
32.
Ejima E,
Rosenblatt JD,
Massari M,
Quan E,
Stephens D,
Rosen CA,
Prager D:
Cell-type-specific transactivation of the parathyroid hormone-related protein gene promoter by the human T-cell leukemia virus type I (HTLV-I) tax and HTLV-II tax proteins.
Blood
81:1017,
1993[Abstract/Free Full Text]
33.
Prager D,
Rosenblatt JD,
Ejima E:
Hypercalcemia: Parathyroid hormone-related protein expression and human T-cell leukemia virus infection.
Leuk Lymphoma
14:395,
1994[Medline]
[Order article via Infotrieve]
34.
Dittmer J,
Gegonne A,
Gitlin SD,
Ghysdael J,
Brady JN:
Regulation of parathyroid hormone-related protein (PTHrP) gene expression. Sp1 binds through an inverted CACCC motif and regulates promoter activity in cooperation with Ets1.
J Biol Chem
269:21428,
1994[Abstract/Free Full Text]
35.
Wake A,
Tanaka Y,
Nakatsuka K,
Misago M,
Oda S,
Morimoto I,
Eto S:
Calcium-dependent homotypic adhesion through leukocyte function-associated antigen-1/intracellular adhesion molecule-1 induces interleukin-1 and parathyroid hormone-related protein production on adult T-cell leukemia cells in vitro.
Blood
86:2257,
1995[Abstract/Free Full Text]
36.
Ishikawa T,
Imura A,
Tanaka K,
Shirane H,
Okuma M,
Uchiyama T:
E-selectin and vascular cell adhesion molecule-1 mediate adult T-cell leukemia cell adhesion to endothelial cells.
Blood
82:1590,
1993[Abstract/Free Full Text]
37.
Motokura T,
Endo K,
Kumaki K,
Ogata E,
Ikeda K:
Neoplastic transformation of normal rat embryo fibroblasts by a mutated p53 and an activated ras oncogene induces parathyroid hormone-related peptide gene expression and causes hypercalcemia in nude mice.
J Biol Chem
270:30857,
1995[Abstract/Free Full Text]
38.
Foley J,
Wysolmerski JJ,
Broadus AE,
Philbrick WM:
Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53.
Cancer Res
56:4056,
1996[Abstract/Free Full Text]
39.
Sakashita A,
Hattori T,
Miller CW,
Suzushima H,
Asou N,
Takatsuki K,
Koeffler HP:
Mutations of the p53 gene in adult T-cell leukemia.
Blood
79:477,
1992[Abstract/Free Full Text]
40.
Cesarman E,
Chadburn A,
Inghirami G,
Gaidano G,
Knowles DM:
Structural and functional analysis of oncogenes and tumor suppressor genes in adult T-cell leukemia/lymphoma shows frequent p53 mutations.
Blood
80:3205,
1992[Abstract/Free Full Text]
41.
McCauley LK,
Rosol TJ,
Merryman JI,
Capen CC:
Parathyroid hormone-related protein binding to human T-cell lymphotropic virus type I-infected lymphocytes.
Endocrinology
130:300,
1992[Abstract/Free Full Text]
42.
Inoue D,
Matsumoto T,
Ogata E,
Ikeda K:
22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus type I-infected T cells.
J Biol Chem
268:16730,
1993[Abstract/Free Full Text]
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Abstract
Introduction
Abstract