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Biomedical subjects

D J Park

Publications and source records attributed to D J Park.

At least 37 records · Page 2Linked to original sources
PubMed2000

The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves' disease.

The goal of this study was to evaluate the clinical significance of the blocking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ovary (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mc1+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in FRTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patients who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Graves' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wild-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean stimulating TSHRAb activities measured by FRTL-5, Mc1+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not different between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T4) levels, or goiter size. However, the prevalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the patients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disease when measured with chimeric receptor expressing cells. Blocking TSHRAb in Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of stimulating TSHRAb activities measured by CHO-hTSHR. The association of blocking TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves' patients is different in those who do and who do not have ophthalmopathy.

Adult↗
PubMed2000

Alteration of MAP kinase pathways after transient forebrain ischemia.

Extracellular regulated kinase (ERK) transduce growth factor signals while c-Jun NH(2)-terminal kinase (JNK) delivers stress signals into the nuclei for regulation of gene expression. These signaling pathways were studied by laser-scanning confocal microcopy and Western blot analysis using phospho-specific antibodies on rat brains that were subjected to 15 minutes transient forebrain ischemia followed by varied periods of reperfusion. Extracellular regulated kinase was activated at 30 minutes and 4 hours of reperfusion in the nuclei and dendrites of surviving dentate gyrus (DG) cells, but not in dying CA1 neurons after ischemia. Tyrosine phosphorylation of Trk kinase, an ERK upstream growth factor receptor, was elevated in the DG tissue, and to a lesser extent in the CA1 region. In addition, phosphorylation of activating transcription factor-2 (ATF-2) and c-Jun was selectively increased in CA1 dying neurons during the late period of reperfusion. These findings suggested that the Trk-ERK signaling pathway might be neuroprotective for dentate granule cells. The activation of ATF-2 and c-Jun pathways in the late period of reperfusion in CA1 dying neurons might reflect damage signals in these neurons. These results suggested that the lack of protective signals acting in concert with the presence of damage signals in CA1 neurons after ischemia might contribute to delayed neuronal death after transient forebrain ischemia.

Activating Transcription Factor 2↗
PubMed2000

Acute cerebral phaeohyphomycosis due to Wangiella dermatitidis accompanied by cerebrospinal fluid eosinophilia.

We report a case of cerebral phaeohyphomycosis due to Wangiella dermaitidis in an immunocompetent adult man. His cerebrospinal fluid (CSF) showed pleocytosis with a high eosinophil count but without peripheral blood eosinophilia. The present case suggested that this black yeast-like fungus should be included when the causes of CSF eosinophilia are considered, even though it is an extremely rare pathogen.

Adult↗
PubMed2000

Cartilage generation using alginate-encapsulated autogenous chondrocytes in rabbits.

In this study, we investigated the possible use of calcium alginate as a matrix for cartilage generation with autogenous chondrocytes, and examined whether the generated cartilage could keep its original volume over time when used as an implant for filling and contour restoration in the host body. Biodegradable, biocompatible, and injectable calcium alginate impregnated with isolated autogenous chondrocytes from the auricle was injected into the gluteus muscle of 12 New Zealand White rabbits. The volume of injected calcium alginate was always 3 mL, and the density of chondrocytes was 10 x 10(6) cells per milliliter. At 4 weeks (short-term period, n = 6) and 20 weeks (long-term period, n = 6) after injection, the histologic findings and the volume of the generated cartilaginous nodules were analyzed. At the time of harvest, 10 of the 12 specimens revealed findings characteristic of natural cartilage. However, histologic examination demonstrated scanty vascular and fibrous tissue ingrowth. Many osteoid matrices, including marrow-like cells, were noted in the vicinity of the neocartilage. The approximate original volume of the injected material was maintained over 20 weeks. These results suggest that although complete cartilage replacement was not always achieved, calcium alginate-autogenous chondrocytes may represent an injectable implant that can generate new autogenous fibro-osteo-cartilaginous tissue for volume augmentation.

Alginates↗
PubMed2000

Incidence of presbycusis of Korean populations in Seoul, Kyunggi and Kangwon provinces.

Presbycusis, a bilateral sensorineural hearing loss caused by changes in the inner ear, is related to multiple factors such as noise exposure and otologic disease. In institute-based studies, we tried to determine the incidence of presbycusis in Korean populations living in Seoul, Kyunggi and Kangwon provinces by gender and age groups. The subjects were people who had visited health promotion centers. Pure tone audiometry was done over 20 years on 6,028 subjects. In a community-based study, the subjects were elderly residents of Kanghwa-do area. There were no obvious factors that could cause hearing impairment in the subjects. For the pure tone audiometry, hearing threshold was obtained by using the six-dimension method. The incidence of presbycusis for subjects aged 65 years and older was 37.8% and 8.3% for > or = 27 dB HL criterion and > or = 41 dB HL criterion, respectively. The incidence increased with age. A statistically significant difference in the hearing threshold was found between men and women aged 65 years or older. No differences were found between the community-based study and the institute- based studies. There was a high incidence (about 40%) of presbycusis among Koreans aged 65 years or older (for > or = 27 dB HL criterion). With an aging population, we anticipate that this report could be used to provide a basic data for the study of presbycusis.

Adult↗
PubMed2000

Comparison of glucose tolerance categories in the Korean population according to World Health Organization and American Diabetes Association diagnostic criteria.

OBJECTIVES: To compare the prevalence and metabolic profiles of glucose tolerance categories according to World Health Organization(WHO) and 1997 American Diabetes Association(ADA) fasting criteria for the diagnosis of diabetes mellitus and impaired glucose metabolism in the Korean population. METHODS: 2251 subjects without previous history of diabetes, who participated in the Yonchon diabetes epidemiology survey in 1993, were classified according to both criteria. The prevalence of glucose tolerance categories and the agreement across all categories of glucose tolerance were calculated. Metabolic characteristics of different glucose tolerance categories were compared. RESULTS: The prevalence of diabetes and impaired fasting glucose(IFG) according to ADA fasting criteria was similar to those of diabetes and impaired glucose tolerance(IGT) according to WHO criteria, respectively. However, 35.5% of the subjects who were diagnosed as diabetes by WHO criteria were reclassified as either IFG or normal fasting glucose (NFG), and 38.5% of diabetic patients according to ADA fasting criteria were IGT or normal glucose tolerance (NGT) by WHO criteria. Only 31.3% of IGT subjects remained as IFG and 62.1% were reclassified as NFG. Similarly, 69.4% of IFG subjects were NGT by WHO criteria. The agreement between the two criteria was poor (K = 0.31). Discordant diabetes groups had higher WHR, systolic and diastolic blood pressure, cholesterol and triglyceride levels than concordant non-diabetes group. Non-diabetes(WHO)/diabetes(ADA) group had higher WHR than diabetes (WHO)/non-diabetes(ADA) group. There were no differences in other metabolic characteristics between the two discordant diabetes groups. IGT/NFG and NGT/IFG group showed higher BMI, WHR, systolic and diastolic blood pressure, cholesterol and triglyceride levels than NGT/NFG group. Metabolic characteristics of IGT/NFG group were not different from those of NGT/IFG group except IGT/NFG subjects were older than NGT/IFG subjects. CONCLUSION: The agreement between WHO and ADA fasting criteria was poor. ADA fasting criteria can detect new diabetic patients and subjects with impaired glucose metabolism who are not classified as diabetes or IGT by WHO criteria. However, a substantial number of subjects, who may have increased cardiovascular risk and/or increased risk for the development of diabetes and its complication, will be missed when using ADA fasting criteria.

Adult↗
PubMed1999

Myeloid transcription factor C/EBPepsilon is involved in the positive regulation of lactoferrin gene expression in neutrophils.

Targeted mutation of the myeloid transcription factor C/EBPepsilon in mice results in gram-negative septic death at 3 to 5 months of age. This study defines the underlying molecular defects in their terminal granulocytic differentiation. The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPepsilon-/- mice. This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria. Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPepsilon-/- mice. While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPepsilon -/- granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase. In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice. The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site. C/EBPepsilon bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it. A mutation in the C/EBP site reduced the activity of the promoter by 35%. Furthermore, overexpression of C/EBPepsilon in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold. In summary, our data implicate C/EBPepsilon as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.

Animals↗
PubMed1999

CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment.

The CCAAT/enhancer binding protein epsilon (C/EBPepsilon) is a nuclear transcription factor expressed predominantly in myeloid cells and implicated as a potential regulator of myeloid differentiation. We show that it was rapidly induced in the acute promyelocytic leukemia (APL) cell line NB4 during granulocytic differentiation after exposure to retinoic acid (RA). Our data suggest that induction of C/EBPepsilon expression was through the retinoic acid receptor alpha (RARalpha) pathway. Reporter gene studies showed that C/EBPepsilon promoter/enhancer activity increased in a retinoid-dependent fashion via the retinoic acid response element (RARE) present in the promoter region of C/EBPepsilon. The RA-induced expression of C/EBPepsilon markedly increased in U937 myelomonoblasts that were induced to express promyelocytic leukemia/RARalpha (PML/RARalpha), but not in those induced to express promyelocytic leukemia zinc finger/RARalpha (PLZF/RARalpha). In retinoid-resistant APL cell lines, C/EBPepsilon either is not induced or is induced only at very high concentrations of RA (>/=10(-6) M). In addition, forced expression of C/EBPepsilon in the U937 myelomonoblastic leukemia cells mimicked terminal granulocytic differentiation, including morphologic changes, increased CD11b/CD66b expression, and induction of secondary granule protein expression. Our data strongly suggest that C/EBPepsilon is a downstream target gene responsible for RA-induced granulocytic differentiation of APL cells.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Metabolic effect of decreasing nonesterified fatty acid levels with acipimox in hyperthyroid patients.

Glucose intolerance is often found in patients with hyperthyroidism, but the pathogenetic mechanisms are not fully understood. Since lipolysis is increased in hyperthyroidism, elevated plasma nonesterified fatty acids (NEFAs) may contribute to abnormal glucose metabolism in hyperthyroidism. The aim of this study was to investigate whether decreasing the plasma NEFA level with acipimox can affect glucose metabolism in hyperthyroidism. We performed an intravenous glucose tolerance test (IVGTT) with acipimox 250 mg or placebo in six untreated hyperthyroid men and six age- and body mass index (BMI)-matched controls. Fasting plasma NEFA levels were significantly higher in the hyperthyroid patients versus the controls (997.0 +/- 303.4 v290.5 +/- 169.1 micromol/L, P < .001). Plasma NEFAs decreased rapidly with acipimox treatment in both controls and hyperthyroid patients. In the controls, the glucose disappearance constant (K(G)) was not different for acipimox treatment versus placebo (2.18 +/- 0.62 v 2.42 +/- 1.00% x min(-1)). In hyperthyroid patients, acipimox treatment increased the K(G) significantly compared with placebo treatment (2.44 +/- 0.84 v 1.58 +/- 0.37% x min(-1), P < .05). Changes in K(G) values with acipimox treatment were inversely correlated with changes in plasma NEFA levels (r = -.65, P < .05). Acipimox treatment increased the acute insulin response (AIR) in hyperthyroid patients (943 +/- 381 v 698 +/- 279 microU/mL x min, P < .05), whereas it did not change the AIR in controls. Changes in the AIR with acipimox treatment correlated significantly with changes in the K(G) (r = .70, P < .05). There was a weak correlation between changes in the AIR with acipimox treatment and changes in plasma NEFA levels (r = -.55, P = .06). In summary, decreasing the plasma NEFA level with acipimox in hyperthyroid patients increases both the K(G) and AIR during an IVGTT. These findings suggest that the abnormal glucose metabolism in hyperthyroidism could be attributed, at least in part, to the increase of plasma NEFA.

Administration, Oral↗
PubMed1999

Two Graves' disease patients who spontaneously developed hypothyroidism after antithyroid drug treatment: characteristics of epitopes for thyrotropin receptor antibodies.

Few reports have identified blocking thyrotropin receptor antibodies (TSHRAbs) as a pathogenic mechanism explaining spontaneous hypothyroidism after antithyroid drug (ATD) treatment of Graves' disease. Here we report 2 Graves' patients who showed different courses of hypothyroidism after ATD treatment. The first patient had Graves' hyperthyroidism and was treated with ATD for 1 year. After a short period of euthyroidism, she developed permanent hypothyroidism with blocking TSHRAb. The second patient became euthyroid after 1 year of ATD treatment. After 3 years, however, she presented with hypothyroidism with blocking TSHRAb activity. Her hypothyroidism was transient, and restoration of euthyroidism was followed by disappearance of blocking TSHRAb. Blocking and stimulating TSHRAbs activities of these 2 patients were serially measured using Chinese hamster ovary (CHO) cells transfected with wild-type human TSHR (CHO-hTSHR) and 2 TSHR chimeras with residues 8-165 (Mc1+2) or 90-165 (Mc2) substituted by equivalent residues of the luteinizing hormone/chorionic gonadotropin receptor (LH/CGR). During their hypothyroid phases, blocking TSHRAbs activities were positive in all 3 kinds of assays and stimulating TSHRAbs activities were negative in CHO-hTSHR or in Mc 1+2 assay. Mc2 stimulating TSHRAb activity was detected in sera of hypothyroid phase of the second patient who had transient hypothyroidism but not in the first whose hypothyroidism was permanent. In these 2 cases, we demonstrate the causative role of blocking TSHRAb in the development of hypothyroidism after ATD treatment in Graves' patients. Interestingly, the difference in the course of blocking TSHRAb-induced hypothyroidism was associated with the difference in epitope reactivities of TRAb during hypothyroid phase that developed after ATD treatment of Graves' disease.

Adult↗
PubMed1999

Adaptive template filtering for signal-to-noise ratio enhancement in magnetic resonance imaging.

In this paper, a local shape-adaptive template filtering is proposed for the enhancement of the signal-to-noise ratio (SNR) without the loss of resolution in magnetic resonance (MR) imaging. Unlike conventional filtering, where the template shape and coefficients are fixed, multiple templates are defined in the proposed algorithm. An optimal template is selected and optimal filtering, based on the template, is applied on a pixel-by-pixel basis. Using the proposed process, edge blurring is minimized and SNR enhancement is maximized by selecting the optimally matched template. Compared to existing two-dimensional (2-D) adaptive linear least square error (LLSE) filters or direction-adaptive recursive filters, the proposed adaptive template filter provides higher SNR and sharper edges for both MR and artificial resolution phantom images.

Algorithms↗
PubMed1998

Cloning, expression, and characterization of a novel guanylate-binding protein, GBP3 in murine erythroid progenitor cells.

We report the molecular cloning of a novel guanylate-binding protein (GBP), termed mouse GBP3 (mGBP3) in Friend virus-induced mouse erythroid progenitor (FVA) cells. The 71-kDa mGBP3 belongs to a family of known GBPs that contain the first two consensus motifs, GXXXXGK(S/T) and DXXG, but lack the third element, (N/T)KXD, found in typical GTP-binding proteins. Recombinant mGBP3 protein, expressed using a baculovirus expression system, binds to agarose-immobilized guanine nucleotides (GTP, GDP and GMP). Moreover, mGBP3 has been found to have an intrinsic GTPase activity with K(m) and Vmax values of 77 +/- 4 microM and 21 +/- 0.5 pmol min-1 microgram-1 of protein, respectively. The mGBP3 is distinct from the other GBPs, in that it does not have an isoprenylation/methylation motif CAAX at the carboxyl terminus. The mGBP3 appears to be localized in the cytosol based on immunofluorescence staining. Although the mGBP3 transcript is expressed to a varying degree in numerous mouse tissues, the message is most abundant in FVA cells. The mGBP3 transcript increases in FVA cells undergoing differentiation to a maximum within a few hours and then decreases to an undetectable level by 24 h. These results, taken together, suggest that mGBP3 is a novel member of a family of guanylate-binding proteins, which plays a role in the erythroid differentiation. The nucleotide sequence reported in this paper has been submitted to the GenBank with accession number U44731.

Amino Acid Sequence↗
PubMed1998

Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.

Cell Division↗
PubMed1998

Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus.

Qualitative changes in mitochondrial DNA (mtDNA), such as mutations and deletions, have been implicated in the pathogenesis of diabetes mellitus. In addition to the qualitative changes, mtDNA is subject to quantitative changes, and is vulnerable to oxidative stress, resulting in both qualitative and quantitative changes. This study was performed to investigate whether quantitative changes in mtDNA occur in non-insulin-dependent diabetes mellitus (NIDDM) patients and also in pre-diabetic subjects. MtDNA content from peripheral blood was measured by slot-blot analysis in 55 NIDDM patients and 29 age- and sex-matched control subjects. We have also analysed the mtDNA copies by quantitative polymerase chain reaction (PCR) method in 23 pre-diabetic subjects who converted to diabetic in 2 years and 22 age- and sex-matched control subjects who remained non-diabetic. Mean mtDNA quantity measured by slot blot method was 35% lower in patients with NIDDM than in control subjects (12.3+/-8.1 vs. 19.1+/-8.2 AU/microg DNA; P < 0.05). MtDNA quantities did not correlate with age, body mass index, duration of diabetes or HbA1c levels. We have also found that the mtDNA copies in subjects who converted to diabetes in 2 years were lower than in controls even before the development of diabetes (102.8+/-41.5 vs. 137.8+/-67.7 copies/pg template DNA P < 0.05). Inverse correlations were noted between mtDNA content and baseline waist hip circumference ratio (WHR) (r = -0.31, P < 0.05), and fasting glucose level (r = - 0.35, P < 0.05), diastolic blood pressure (r = -0.36, P < 0.05), and WHR (r = -0.40, P < 0.01) after development of diabetes. In conclusion, we demonstrate that the content of mtDNA decreases in peripheral blood of patients with NIDDM and the lower mtDNA levels precede the development of diabetes.

Biomarkers↗
PubMed1998

EGF-stimulated aldosterone secretion is mediated by tyrosine phosphorylation but not by phospholipase C in cultured porcine adrenal glomerulosa cells.

We examined the effect of EGF and angiotensin II (AII) on the formation of inositol phosphates and aldosterone secretion, and observed the role of tyrosine phosphorylation in EGF or AII-mediated aldosterone secretion. As cultured glomerulosa cells were incubated with increasing concentrations of EGF (0.01-100 ng/mL), aldosterone secretion increased and reached a plateau at EGF concentration of 10-50 ng/mL. Although EGF alone did increase aldosterone secretion in glomerulosa cells, it did not enhance AII-induced aldosterone secretion when both EGF and AII were added. EGF-induced tyrosine phosphorylation peaked at around 1 min after stimulation and at a concentration of 10-50 ng/mL. AII stimulated tyrosine phosphorylation, but the stimulatory effect was less than that observed in the presence of EGF. Although the latter induced tyrosine phosphorylation of various proteins, it failed to stimulate the formation of inositol phosphates. On the other hand, AII stimulated the production of inositol phosphates in a dose-dependent manner, with maximal stimulation at 10(-8)M. The addition of 10 ng/mL EGF did not affect the AII-induced formation of inositol phosphates. In conclusion, EGF-stimulated aldosterone secretion might be mediated by tyrosine kinase. However, since EGF did not stimulate inositol phospholipid hydrolysis in cultured porcine adrenal glomerulosa cells, its effect does not seem to be mediated by phospholipase C.

Aldosterone↗
PubMed1997

Folate deficiency delays the onset but increases the incidence of leukemia in Friend virus-infected mice.

Clinical studies have indicated that folate deficiency may enhance the development of various malignancies. In animal studies that examined the effect of folate deficiency on malignancies, conflicting results have been reported. In some studies, folate deficiency increased the development and growth of malignant tumors; in others, it decreased the development and growth of malignancies. We examined the effect of transient folate deficiency on the development of leukemia in mice infected with the anemia-inducing strain of Friend leukemia virus. Friend virus disease can be considered as a model for human acute leukemias that are preceded by a preleukemic period. These include leukemias that develop in patients who received previous chemotherapy and/or radiation therapy, as well as patients with chronic granulocytic leukemia or myelodysplasia. Folate deficiency around the time of Friend virus-infection delayed the onset but increased the incidence of leukemia. The rates of rearrangement of the Spi-1 (PU.1 ) oncogene by provirus integration and alteration of the p53 tumor-suppressor gene were the same in leukemia cell lines derived from folate-deficient mice as they were in cell lines from control mice. These results indicate that folate deficiency did not exert its enhancement of leukemogenesis through changes in either Spi-1 or p53, even though these two genes have been found to be the most frequently altered ones in Friend virus-induced leukemias. Our results suggest that folate deficiency may enhance the development of acute leukemia in patients who are at high risk for this disease.

Animals↗