Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 kappaB (RANK) ligand gene correlated with hypercalcemia. ATL cells from patients with hypercalcemia, which highly expressed the transcripts of the RANK ligand (RANKL) gene, induced the differentiation of human hematopoietic precursor cells (HPCs) into OCLs in vitro in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, ATL cells from patients without hypercalcemia did not induce such differentiation, suggesting that the induction of the differentiation correlated with the expression of the RANKL gene in ATL cells. Cell differentiation was suppressed by osteoprotegerin/Fc, an inhibitor of RANKL, indicating that such differentiation occurred through the RANK-RANKL pathway. In addition, direct contact between ATL cells and HPCs was essential for the differentiation, suggesting that not the soluble form but membrane-bound RANKL played a role in this process. These results strongly suggested that ATL cells induce the differentiation of HPCs to OCLs through RANKL expressed on their surface, in cooperation with M-CSF, and ultimately cause hypercalcemia.
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PMID:Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. 1178 Dec 48

Polycythemia vera (PV) is known to occasionally transform into acute leukemia. Administration of alkylating agents seems to be associated with an increased risk of leukemic transformation of PV. Hypercalcemia is a serious complication of malignancies, but it is uncommon in acute leukemia. In the majority of malignancies with hypercalcemia, elevated parathyroid hormone-related protein (PTHrP) is thought to be the main cause of hypercalcemia. We report a rare case of megakaryoblastic transformation of PV with hypercalcemia. A 62-year-old man was diagnosed as having PV in 1983, and he had received ranimustine and busulfan. He developed acute megakaryoblastic leukemia 17 years after the initial diagnosis of PV. Serum calcium was elevated, the serum level of intact parathyroid hormone (PTH) was suppressed, and the level of intact PTHrP was slightly elevated. He had no lytic bone lesions; however, uncoupling of bone turnover due to an increase in bone resorption and a decrease in bone formation was detected by using biochemical markers. Since the level of PTHrP was slightly elevated from the normal value, we speculated that PTHrP produced in the local field by leukemic cells might have been more abundant than circulating PTHrP. Pamidronate and adrenocortical hormone were effective in reducing the serum calcium level. However, the patient died shortly after the start of induction chemotherapy. The prognosis of cases of PV that has transformed into acute leukemia is generally poor because the majority of such cases are refractory to chemotherapy.
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PMID:Megakaryoblastic transformation of polycythemia vera with hypercalcemia. 1245 9

Human T cell leukaemia virus type I (HTLV-I) is known to be involved in late-onset chronic polyarthritis as HTLV-I-associated arthropathy. However, it is unclear whether HTLV-I infection could modify the pathophysiology of osteoarthritis (OA). In this study we compared several inflammatory cytokines, such as C-terminal parathyroid hormone-related peptide (C-PTHrP), soluble interleukin-2 receptor (sIL-2R) and interleukin (IL)-6, and an osteo-destruction marker, deoxypyridinoline, in synovial fluid (SF) samples obtained from 22 HTLV-I carriers and 58 control non-carrier patients with OA. These patients were diagnosed clinically and radiographically with primary OA affecting one or both knee joints, and were similar with regard to age, sex and clinical symptoms. We also performed histopathological examination as well as immunohistochemistry of HTLV-I-derived Tax protein in eight synovial tissues taken from carrier patients. C-PTHrP in SF was significantly higher in HTLV-I carriers (287 +/- 280 pM) than in non-carriers (69 +/- 34 pM), and the concentration in 13 carriers was above the upper range of OA. In HTLV-I carriers, the concentrations of sIL-2R (741 +/- 530 IU/ml), IL-6 (55 +/- 86 ng/ml) and deoxypyridinoline (3.1 +/- 1.8 nM) were higher than in non-carriers (299 +/- 303, 2.5 +/- 4.0, 0.96 +/- 1.0, respectively), and correlated positively with C-PTHrP. C-PTHrP, sIL-2R and IL-6 concentrations in SF positive for IgM antibody against HTLV-I antigen, a marker of persistent viral replication, were higher than of IgM-negative SF. Histologically, five and two synovia showed mild and moderate synovial proliferation with or without some degree of inflammatory reaction, respectively, and could not be distinguished from OA. Tax-positive synoviocytes were observed sparsely in all samples, and often appeared frequently in actively proliferating regions. Our results suggest that although HTLV-I infection does not necessarily worsen the clinical outcome and local synovitis, the virus can potentially modify the pathophysiology of OA by increasing the inflammatory activity in a subset of carrier patients, especially those with IgM antibody. Longitudinal studies are required to assess the association between HTLV-I infection and OA.
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PMID:Altered expression of inflammatory cytokines in primary osteoarthritis by human T lymphotropic virus type I retrovirus infection: a cross-sectional study. 1522 70

Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in alpha1-acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute-phase reactions, whereas anti-PTHrP antibody affected neither proinflammatory cytokine production nor acute-phase reactions. Nevertheless, tumor resection and administration of anti-PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti-PTHrP antibody was associated with increased food consumption; increased body weight from anti-PTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP-induced wasting syndrome.
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PMID:Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts. 1580 Sep 41

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy seen in the majority of adult T-cell leukemia/lymphoma (ATLL) patients with human T-cell lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 Tax has been shown to complex with ETS-1 and SP1 to transactivate the PTHrP P3 promoter. Previously, we established a SCID/bg mouse model of human ATL with RV-ATL cells and showed that PTHrP expression was independent of Tax. In this study, we report an inverse correlation of PTHrP with tax/rex mRNA in multiple HTLV-1-positive cell lines and RV-ATL cells. Stimulation of Jurkat T cells with PMA/ionomycin upregulated the PTHrP P3 promoter by a previously characterized Ets binding site and also induced protein/DNA complex formation identical to that observed in RV-ATL cells. Further, we provide evidence that cotransfection with Ets-1 and constitutively active Mek-1 in HTLV-1-negative transformed T cells with stimulation by PMA/ionomycin not only resulted in a robust induction of PTHrP P3 but also formed a complex with ETS-1/P3 EBS similar to that in ATLL cells. Our data demonstrate that transcriptional regulation of PTHrP in ATLL cells can be controlled by T-cell receptor signaling and the ETS and MAPK ERK pathway in a Tax-independent manner.
Leukemia 2005 Jul
PMID:Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma. 1588 57

Our hypothesis was that combinations of radioprotectors would be more effective than individual agents in minimizing the effects of radiation on the growth plate after single-fraction hind-limb irradiation of Sprague-Dawley rats. At 2 days postirradiation, the decrease in parathyroid hormone-related protein and parathyroid hormone receptor 1 expression in the irradiated growth plate transitional and hypertrophic zones was reversed in both of the combination groups but persisted in the groups treated with the individual drugs. By 2 weeks, positive findings unique to the combination-treatment animals included greater mean proliferation in the irradiated growth plate than on the contralateral side, smaller limb length discrepancies, reversal of the increased overall matrix area fraction, and reversal of the usual deficiency in Indian hedgehog staining in the irradiated hypertrophic zone. While all treatments had a positive effect in reversing the decrease in B-cell leukemia 2 protein and coincident increase in Bax previously observed 2 weeks postirradiation, the two combination groups had a more robust effect. Combinations of radioprotectors may achieve their beneficial additive effects in the growth plate by decreasing the usual early drop in parathyroid hormone-related protein and parathyroid hormone receptor 1 after irradiation, resulting in a cascade of parathyroid hormone-related protein-mediated events.
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PMID:Combination radioprotectors maintain proliferation better than single agents by decreasing early parathyroid hormone-related protein changes after growth plate irradiation. 1649 24

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-kappaB (NF-kappaB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Tax-expressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-kappaB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-kappaB p50/p50 alone and p50/c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-kappaB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-kappaB activation and also suggest a Tax-independent mechanism of activation of PTHrP in ATLL.
Leukemia 2007 Aug
PMID:Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-kappaB in adult T-cell leukemia/lymphoma. 1755 73

Human T cell lymphotrophic virus type-1 infection is endemic in the Afro-Caribbean community in Britain, with carriage rates of about 3%. Although there is a long latency, carriers have a 1-5% chance of developing adult T cell leukaemia/lymphoma, a condition frequently complicated by marked and refractory hypercalcaemia, and with a poor prognosis. We present the case of an elderly Jamaican woman with severe hypercalcaemia and a raised PTHrP who was found to have lymphoma and was positive for HTLV-1.
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PMID:Severe hypercalcaemia and lymphoma in an HTLV-1 positive Jamaican woman: a case report. 1765 86

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
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PMID:Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia. 1942 77

A case of adult acute lymphoblastic leukaemia is reported. A 35-year-old male presented with an osteolytic lesion of the mandible. There was no definitive involvement in other craniofacial bones. A panoramic radiograph taken 4 months previously showed no bony involvement. A complete blood count showed a slightly decreased red blood cell count, but normal white blood cell count, white blood cell differential count and platelet count. Routine chemistry revealed hypercalcemia with an increased level of parathyroid hormone-related protein. Histopathological examination of bone marrow biopsy confirmed the diagnosis of acute lymphoblastic leukaemia.
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PMID:Osteolytic mandible presenting as an initial manifestation of an adult acute lymphoblastic leukaemia. 2172 11


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