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)

In 95 leukaemic cell samples from 66 patients with acute myelogenous leukaemia (AML) (47 de novo and 19 secondary AML) telomerase activity was determined and the expression of the telomerase components: telomerase reverse transcriptase (hTERT), telomerase RNA template (hTR) and telomerase-associated protein (TP1) evaluated by RT-PCR. Compared to peripheral blood mononuclear cells (PBMC) from normal adult 87% (82/95) of patient samples exhibited elevated telomerase activity hTERT, but not hTR and TP1 expression strongly correlated with the levels of telomerase activity (r=0.47, P<0.0001). The levels of telomerase activity were significantly higher at time of relapse or progression than at time of diagnosis (P=0.003), and correlated to CD34 expression and chromosomal abnormalities of leukaemic cells (P=0.01 and P=0.001 respectively). The rate and duration of complete remission (CR) did not correlate with the levels of telomerase activity at diagnosis. Among eight patients in first relapse, however, two of three with low levels of telomerase activity re-entered CR. whereas none of five patients with high telomerase activity achieved a second CR. Taken together, telomerase activation/up-regulation in AML is a disease progression-associated event. Undifferentiated status and chromosomal aberration also lead to the up-regulation of telomerase activity in AML.
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PMID:Telomerase activity and the expression of telomerase components in acute myelogenous leukaemia. 975 73

Activation of telomerase is essential for in vitro cellular immortalization and tumorigenesis. In the present study, we investigated telomerase activation and its implications in plasma cell dyscrasias including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plasma cell leukaemia (PCL). All 5 patients with MGUS exhibited normal levels of telomerase activity in their plasma cells. Elevated telomerase activity was found in the samples from 21/27 patients with MM and 4/4 with PCL. In addition, 4 myeloma cell lines all expressed high levels of telomerase activity. The expression of telomerase reverse transcriptase (hTERT) and telomerase RNA template (hTER) was positively associated with the levels of telomerase activity in MM/PCL. Tankyrase expression was upregulated, concomitant with the induction of hTERT and activation of telomerase in MM/PCL. The present findings indicate that MGUS cells may not be immortalized and that activation of telomerase plays a role in the malignant transformation from MGUS to MM.
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PMID:Telomerase activity in plasma cell dyscrasias. 1123 81

Human telomerase reverse transcriptase (hTERT) is considered a potential target for cancer immunotherapy because it is preferentially expressed in malignant cells. hTERT-derived peptides carrying motifs for HLA-A24 (HLA-A*2402), the most common allele among Japanese and also frequently present in persons of European descent, were examined for their capacity to elicit antileukemia cytotoxic T lymphocytes (CTLs). Two of the 5 peptides tested, VYAETKHFL and VYGFVRACL, appeared capable of generating hTERT peptide-specific and HLA-A24-restricted CTLs. The CD8(+) CTL clones specific for these hTERT peptides exerted cytotoxicity against leukemia cells in an HLA-A24-restricted manner. This cytotoxicity was inhibited by the addition of hTERT peptide-loaded autologous cells, suggesting that hTERT is naturally processed in leukemia cells and that hTERT-derived peptides are expressed on these cells and are recognized by CTLs in the context of HLA-A24. Taken together with the currently identified HLA-A2-restricted CTL epitopes derived from hTERT, identification of new CTL epitopes presented by HLA-A24 increases the feasibility of immunotherapy for leukemia using hTERT-derived peptides.
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PMID:Identification of human telomerase reverse transcriptase-derived peptides that induce HLA-A24-restricted antileukemia cytotoxic T lymphocytes. 1131 88

CD4+ T cells play critical roles in initiating, regulating, and maintaining antitumor immune responses. One way to improve current tumor vaccines that mainly induce CTLs would be to activate antigen-specific CD4+ T cells that recognize MHC class II restricted tumor associated antigens. Human telomerase reverse transcriptase (hTRT) is preferentially expressed by various tumors and, therefore, could be a universal tumor antigen. In this study, we used a combined approach of using the prediction software TEPITOPE to select class II epitope candidates and in vitro T-cell biological analysis to identify class II-restricted epitope(s) in hTRT. We first identified several HLA-DR7-restricted class-II epitope candidates in hTRT by examining human T-cell responses to synthetic peptides. We then characterized these HLA-DR7-restricted hTRT epitope candidates by establishing and analyzing peptide-specific T-cell clones. It was demonstrated that CD4+ T cells specific for the HLA-DR7-restricted hTRT(672) epitope (RPGLLGASVLGLDDI) can respond to naturally processed hTRT proteins. Furthermore, the hTRT(672)-specific T cells recognized hTRT antigen from various tumors, including prostate cancer, breast cancer, melanoma, and leukemia. Thus, the identification of the naturally processed HLA-DR7-restricted hTRT epitope, together with the previous finding of class I-restricted hTRT epitopes, provide a basis for the combined application of class I- and II-restricted hTRT epitopes to induce potent, long-term CD4+ and CD8+ T-cell responses against a broad spectrum of tumors.
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PMID:Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells. 1198 Jun 55

Human telomerase, a cellular reverse transcriptase specifically activated in most malignant tumors and usually inactive in normal somatic cells, plays an important role in immortalization and tumorigenesis. Early reports have indicated that terminal differentiation of various cells is associated with a rapid inhibition of telomerase activity, preceded by a down-regulation of telomerase reverse transcriptase (hTERT) mRNA. Recently, we have shown that telomerase can be repressed by all-trans retinoic acid (ATRA) independently of terminal maturation during long-term ATRA treatment of the maturation-resistant promyelocytic leukemia cell line (NB4-R1), leading to shortening of telomeres and cell death, events overcome by ectopic hTERT expression. Here, we report the isolation of a variant of NB4-R1 cells (NB4-R1(SFD)), which bypasses this death step, because of a re-activated telomerase, despite the continuous presence of ATRA. While unresponsive to a long-term maturation independent regulation of telomerase by ATRA, these cells retain a functional pathway of telomerase down-regulation associated with retinoid-induced maturation. These findings reinforce the notion that two distinct pathways of telomerase regulation by retinoids co-exist in APL cells. Noteworthy, we show that the slow developing mechanism, that causes death of maturation-resistant cells, is subjected to a new type of retinoid-resistance as yet not understood.
Leukemia 2002 May
PMID:A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation. 1198 43

Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, hTERT repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies.
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PMID:Inactivation of hTERT transcription by Tax. 1280 80

Telomeres play an important role in the proliferation and senescence of normal and malignant cells. To test the role of telomerase in acute myeloid leukemia (AML), we expressed the telomerase reverse transcriptase (hTERT) gene, a dominant-negative hTERT (DN-hTERT) (D868A, D869A) gene, or a gene encoding green fluorescence protein (GFP) in the leukemia cell line K562 and in primary AML cells from different patients, using retroviral vectors. Cells transduced with hTERT exhibited elevated levels of telomerase activity compared to GFP controls, whereas cells expressing DN-hTERT had decreased telomerase activity. K562 populations transduced with DN-hTERT showed reduced clonogenicity, telomere dysfunction and increased numbers of apoptotic cells compared to GFP- or hTERT-transduced cells. Two of four clones transduced with DN-hTERT died after 30 and 53 population doublings, respectively. Transduced AML cells were tested in primary colony-forming unit (CFU) and suspension culture assays. Relative to hTERT- and GFP-transduced controls, AML cells transfected with DN-hTERT produced fewer CFU and showed lower engraftment after transplantation into sublethally irradiated beta(2)-m(-/-) nonobese diabetic/severe combined immunodeficient mice. We conclude that telomerase is limiting the growth of the leukemic cell line K562 and primary AML progenitor cells. Our data warrant further studies of the therapeutic use of telomerase inhibitors in AML.
Leukemia 2003 Dec
PMID:Telomerase is limiting the growth of acute myeloid leukemia cells. 1456 14

An effective tumor vaccine may require the induction of both CTL and T-helper (Th) cell responses against tumor-associated antigens. Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of cancer cells and thus is a potential target for tumor vaccines. We therefore sought to identify promiscuous Th epitopes in hTERT, which can be presented by more than one MHC class II allele. Each of 10 peptides derived from hTERT that were predicted to bind to MHC class II molecules was found to be able to induce primary human T-cell responses in vitro. We then established CD4(+) T-cell clones specific for these peptides and found that only hTERT(766) (LTDLQPYMRQFVAHL)-specific CD4(+) Th cells were effective in recognizing naturally processed hTERT antigen. We further found that the naturally processed epitopes hTERT(766) and hTERT(672) (which was identified previously) were promiscuous and capable of inducing CD4(+) T-cell responses in the context of several commonly found HLA-DR alleles, including DR1, DR7, and DR15 for hTERT(672), and DR4, DR11, and DR15 for hTERT(766). We further demonstrated that immunization of humanized HLA-DR4 transgenic mice with hTERT(766) peptide elicited antigen-specific Th responses that can recognize the antigenic peptides derived from hTERT protein and various hTERT-positive tumors, such as breast cancer, melanoma, and leukemia. It was also shown that T-cell precursors specific for the naturally processed epitopes are part of the T-cell repertoires in healthy donors and prostate cancer patients. Thus, these promiscuous, naturally processed Th epitopes in hTERT could be used to develop improved cancer vaccines through the simultaneous stimulation of CTL and Th cells against a broad spectrum of hTERT-positive tumors.
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PMID:Human telomerase reverse transcriptase-specific T-helper responses induced by promiscuous major histocompatibility complex class II-restricted epitopes. 1458 45

Telomerase is active in immature somatic cells, but not in differentiated cells. However, the mechanism by which telomerase is regulated in relation to cell differentiation is not well understood. In this study, the human erythroid leukemia cell line K562 was induced to differentiate into megakaryocytes by TPA and into erythroid by STI571. The human acute myeloblastic leukemia cell line HL60 was also induced to differentiate into monocytes by TPA. Telomerase activity, the expression of human telomerase reverse transcriptase, hTERT, and the cell cycle were examined. TPA induced a transient increase in telomerase activity during the megakaryocytic differentiation while the message of hTERT decreased gradually throughout the same period. This suggests the existence of a regulatory mechanism other than transcription of hTERT. Cell cycle analysis revealed that cells in G(2)/M phase increased in number in accordance with the changes in telomerase activity. Pretreatment with PKC inhibitors inhibited the megakaryocytic differentiation, transient increase in telomerase activity, and G(2)/M arrest. These results suggest that PKC acts as a transient post-translational activator of telomerase during megakaryocytic differentiation.
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PMID:Transient posttranslational up-regulation of telomerase activity during megakaryocytic differentiation of K562 cells. 1475 Dec 43

Telomerase activity and the expression of telomerase subunits (for example, telomerase reverse transcriptase and telomerase associated protein 1 and telomerase RNA component) of peripheral white blood cells were detected in the patients with acute myelogenous leukaemia (AML) and the correlation between telomerase activity and the expression of telomerase subunits was observed. In 94 peripheral white blood cells from 18 healthy volunteers and 76 patients with AML, including 31 AML at initial presentation, 24 at relapse and 21 at complete remission, the telomerase activity and telomerase subunits mRNA or RNA were detected by PCR-ELISA and RT-PCR respectively. The results showed that the positive rate of telomerase from patients with AML at initial presentation, at relapse and at complete remission was 74.1%, 79.2% and 4.8% respectively. The positive rate of telomerase reverse transcriptase mRNA from healthy volunteers, AML at initial presentation, AML at relapse and AML at complete remission was 5.6%, 80.6%, 83.3% and 9.5% respectively. The positive rate of telomerase associated protein 1 mRNA and telomerase RNA component in all samples were 100%. It was suggested that the up-regulation of telomerase activity and the expression of telomerase reverse transcriptase is correlated closely with the occurrence and relapse of AML, so telomerase activity and the expression of telomerase reverse transcriptase may be used to estimate the curative effect and predict relapse of AML. Moreover, the up-regulation of telomerase activity is correlated with the expression of telomerase reverse transcriptase significantly.
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PMID:Detection of telomerase activity and the expression of telomerase subunits in the patients with acute myelogenous leukaemia. 1516 14


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