Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+) T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemogenesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the expression of distinct cellular genes. Alterations in the expression levels of unknown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked to Tax transformation and ATL leukemogenesis, this study systematically compared the gene expression of cultured cells from patients with acute ATL with that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These include a dual-specific protein phosphatase (PAC1), an interferon-inducible factor (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) signaling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309--specific antiapoptotic activity and the proapoptotic effect of inhibitors of I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apoptosis in ATL cells and could substantially contribute to their growth. (Blood. 2001;98:1150-1159)
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PMID:Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309. 1149 64

Human T-cell leukaemia virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATL) carries a very poor prognosis due to an intrinsic resistance of leukaemic cells to conventional or even high doses of chemotherapy and to an associated severe immunosuppression. Therefore, the potential role of conventional chemotherapy, high dose chemotherapy with autologous or allogeneic bone marrow transplantation remains to be defined. Important progress was achieved in the treatment of ATL with the combination of zidovudine (AZT) and interferon-alpha (IFN) which produces a high response rate in ATL patients with minimal side effects. This treatment seems to prolong the survival of patients much more than intensive chemotherapy. The success of this potentially anti-retroviral approach in the treatment of ATL suggests the existence of continuous HTLV-I replication in vivo. These encouraging results may be improved by the use of higher doses of AZT and IFN combined with other anti-retroviral agents. However, since cure seems still elusive, new therapeutic approaches or new combinations are required. For example, biological mediators such as retinoid acid, which induces apoptosis of ATL cells in vitro, may reduce drug resistance and stimulates immunity to restore anti-tumour activity against ATL cells. Alternatively, immunotherapy with anti-interleukin-2 receptor monoclonal antibodies or injection of cytotoxic T-cells directed against virus antigens could be interesting approaches which may merit further investigations in the near future. Finally, the recent demonstration that the combination of arsenic trioxide (As) and IFN induces a specific degradation of the viral transactivator Tax followed by cell cycle arrest and apoptosis of HTLV-I positive cells may constitute a valuable addition to ATL treatment.
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PMID:Treatment of adult T-cell leukaemia/lymphoma: current strategy and future perspectives. 1152 May 75

Although the viral transactivator Tax has been established as an essential effector of HTLV-I-mediated oncogenesis, its exact role(s) in the pathogenesis of HTLV-I-associated diseases, which include both a neurodegenerative pathology and leukemia/lymphoma, remains to be clarified. It was recently advanced that dysregulation of the apoptotic process can lead to pathophysiological changes which result in either degenerative diseases or cancer. As the apoptotic potential of Tax is still debated, we addressed this question by testing the susceptibility of Tax(+) and Tax(-) murine fibroblasts to apoptosis under conditions of growth factor withdrawal or treatment with TNFalpha, which trigger apoptosis through different pathways, i.e., mitochondrial and receptor-mediated pathways, respectively. Results showed that Tax-expressing cells are protected from apoptotic death induced by serum deprivation but are sensitive to TNFalpha-mediated apoptosis, suggesting that Tax expression has different effects on cell death, depending on the apoptotic stimulus used. Analysis of the mechanism(s) involved in the resistance to serum depletion-induced apoptosis indicated that Tax(+) cells do not undergo release of cytochrome c from the mitochondrial intermembrane space or redistribution of Bax from the cytosol to mitochondria, two phenomena critical to the mitochondrial apoptotic pathway.
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PMID:Block of a mitochondrial-mediated apoptotic pathway in Tax-expressing murine fibroblasts. 1157 Aug 17

Adult T-cell leukemia (ATL) is associated with prior infection with human T-cell leukemia virus type 1 (HTLV-1). TAX, the major transactivator of HTLV-1, has been implicated in the immortalization of infected T-cells, but molecular mechanisms of in vivo malignant cell transformation induced by HTLV-1 remain unclear. To investigate the role of TAX in the monoclonal proliferation of ATL cells, we determined the nucleotide sequence of tax DNA clones obtained from 6 ATL patients and analysed the biological function of their products. We found that ATL cells from 2 of these patients possessed tax with a nonsense or frame-shift mutation resulting in the premature termination of its protein product, which was no longer functional. This strongly argued against an indispensable role of TAX for the maintenance of ATL cells in vivo. On the other hand, the frequency of nucleotide substitutions found in non-functional tax DNA clones from these patients was significantly lower than those in functional tax DNA clones from the others, suggesting a role for TAX in the genome instability of infected cells. Although mismatch repair defects in the microsatellite markers, including those in hMSH3, hMSH6, BAX, TGF-beta RII, and E2F4 genes, were infrequent, we found an increase in the number of CAG repeats of the E2F4 microsatellite marker in 1 patient. These findings indicate that while TAX may be a necessary prerequisite for malignant transformation of infected cells, it is not essential for the maintenance of ATL cells in vivo.
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PMID:HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia. 1172 64

Previously, we have shown that interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)-induced differentiation of the myeloid cell line M1 was associated with a rapid increase in the level of mRNA encoding the signaling adaptor protein, SKAP55R. Furthermore, enforced over-expression of SKAP55R in primary bone marrow cells inhibited colony growth. In this study, we have identified the cis-acting elements that control SKAP55R transcription in myeloid cells. The 980 bp genomic sequence upstream of the transcriptional start site was cloned into a GFP reporter vector for transient (293 cells) or stable (M1 cells) transfection assays. This region contained cis-acting elements necessary for transcriptional activity in unstimulated 293 cells (10-fold higher levels than the control vector) or unstimulated M1 cells (two-fold higher levels). Significant LIF-induced transcription was observed in M1 (3.4-fold induction, P < 0.001), but not 293 cells. Deletion reporter constructs defined a promoter region (-317/-137) essential for the transcriptional activity in M1 cells. This region contained a CCAAT element recently implicated in IL-6/LIF-induced transcriptional regulation of junB in M1 cells. Mutation of the CCAAT element (-250/-246) significantly reduced both basal and LIF-induced transcription (P < 0.01). Electrophoretic mobility shift assays demonstrated that NF-Y bound to the CCAAT element of both SKAP55R and junB. These results suggest NF-Y binding may be a common mechanism of IL-6/LIF-regulated transcription in myeloid cells.
Leukemia 2001 Dec
PMID:NF-Y regulates LIF-induced transcription of the signaling adaptor SKAP55R in myeloid cells. 1175 15

Alterations of the proto-oncogene MLL (mixed lineage leukemia) are characteristic for a high proportion of acute leukemias, especially those occurring in infants. The activation of MLL is achieved either by an internal tandem duplication of 5' MLL exons or by chromosomal translocations that create chimeric proteins with the N-terminus of MLL fused to a variety of different partner proteins. A domain of MLL with significant homology to the eukaryotic DNA methyltransferases (MT domain) has been found to be essential for the transforming potential of the oncogenic MLL derivatives. Here we demonstrate that this domain specifically recognizes DNA with unmethylated CpG sequences. In gel mobility shifts, the presence of CpG was sufficient for binding of recombinant GST-MT protein to DNA. The introduction of 5-methylCpG on one or both DNA strands precluded an efficient interaction. In surface plasmon resonance a KD of approximately 3.3 x 10(-8) M was determined for the GST-MT/DNA complex formation. Site selection experiments and DNase I footprinting confirmed CpG as the target of the MT domain. Finally, this interaction was corroborated in vivo in reporter assays utilizing the DNA-binding properties of the MT domain in a hybrid MT-VP16 transactivator construct.
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PMID:The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. 1184 7

Human T cell leukemia virus type 1 (HTLV-1) encodes a transforming protein, Tax. Tax is a promiscuous viral transactivator involved in both cell growth and death control. We have previously shown that Tax sensitizes cells to apoptosis induced by DNA-damaging agents and this report further characterizes the Tax-mediated apoptosis pathway. We found that Tax-mediated apoptosis in response to UV irradiation was inhibited by Bcl-2 and Bcl-X(L) overexpression and by treatment with the caspase inhibitor z-VAd-FMK. Since Tax has been shown to functionally inactivate the apoptosis regulator p53, the effect of Tax on apoptosis in the absence of p53 was examined. In these studies, Tax sensitized p53-negative cells to apoptose, suggesting that Tax can mediate a p53-independent form of apoptosis. In addition, cells expressing both Tax and p53 displayed higher levels of apoptosis than cells expressing either protein alone, suggesting that the apoptosis-inducing activities of Tax and p53 are not completely overlapping. These observations demonstrate that Tax can utilize a p53-independent mechanism to induce apoptotic cell death following UV irradiation.
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PMID:p53-independent induction of apoptosis by the HTLV-I tax protein following UV irradiation. 1187 98

The role of angiogenesis in the growth and metastasis of solid tumors is well established. However, the role of angiogenesis in hematologic malignancies was only recently appreciated. We show that HTLV-I-transformed T cells, but not HTLV-I-negative CD4(+) T cells, secrete biologically active forms of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and, accordingly, induce angiogenesis in vitro. Furthermore, fresh ATL leukemic cells derived from patients with acute ATL produce VEGF and bFGF transcripts and proteins. The viral transactivator Tax activates the VEGF promoter, linking the induction of angiogenesis to viral gene expression. Angiogenesis is associated with the adhesion of HTLV-I-transformed cells to endothelial cells and gap junction-mediated heterocellular communication between the 2 cell types. Angiogenesis, cell adhesion, and communication likely contribute to the development of adult T-cell leukemia-lymphoma and represent potential therapeutic targets.
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PMID:Human T-cell lymphotropic virus type 1-transformed cells induce angiogenesis and establish functional gap junctions with endothelial cells. 1196 7

Patients with secondary myelodysplasias and acute myeloid leukemias (MDS/AML) frequently exhibit interstitial deletions of the chromosome-5q resulting in hemizygous loss of the transcription transactivator Smad5. Smad5 is a member of the signal transducer family conveying the pleiotropic TGF-gb/BMP cytokine signals with roles in development, cell growth control, and tumor progression. Here we present a study of the Smad5 expression and its functional role in leukemia cell lines as well as in primary CD34+ progenitors of MDS/AML patients and healthy individuals. Consistent Smad5 gene expression in these cell types and the gradual increase in its mRNA and protein levels in a model of induced erythroid differentiation of murine erythroleukemia (MEL) cells suggest a role of the gene in hematopoiesis. We show that bone morphogenetic protein 4 (BMP4) directs Smad5 activation in human hematopoietic cells, as monitored at the levels of protein phosphorylation, nuclear translocation, and specific transcription response. In vitro induction of normal human CD34+ cells by BMP4 results in significantly increased proliferation of erythroid progenitors (BFU-E) and formation of glycophorin-A+ cells, whereas perturbation of Smad5 expression by antisense oligonucleotides causes significantly decreased rates of BMP4-induced erythroid differentiation. We have not detected any effects of Smad5 inhibition on BMP4-stimulated progenitors of the granulocyteNmacrophage lineage. We propose that the BMP4/Smad5 signal transduction pathway activates hematopoietic differentiation programs that may be impaired in anemia manifestations in MDS and AML patients with Smad5 haploinsufficiency.
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PMID:Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. 1206 18

The promyelocytic leukaemia (PML) gene, which encodes a transformation and growth suppressor, was found to regulate transcription and apoptosis. PML was first identified at the chromosomal translocation break-points t(15;17) of acute promyelocytic leukaemia and the gene product may mediate cell-cycle control and apoptosis. PML was found to interact with the co-transactivator CREB binding protein (CBP) and the apoptotic-modulator Bax. To determine if PML, CBP and Bax may be involved in solid tumours, such as the nasopharyngeal carcinoma (NPC), a rare neoplasia that is prevalent in Southern China, the expression of these proteins and the proliferation marker Ki-67 was analysed by immunohistochemical staining. Expression of PML in the PML-oncogenic domain (POD) or nuclear bodies in most NPC was inversely correlated with the expression of Ki-67. In addition, based on PML expression patterns in NPC three subtypes could be identified, namely, Subtype-1, with strong PML expression in POD structures and with low Ki-67 staining; Subtype-2, where PML was expressed in a homogeneously diffused pattern, but with a low intensity in the tumour cells; while Ki-67 was expressed in a moderate number of cells and Subtype-3, where the majority of tumour cells were PML-negative, while a considerable number of tumour cells were strongly labelled with Ki-67. Furthermore, CBP was present in most of the NPC cells with moderate-strong nuclear staining, while the expression in non-tumour cells were relatively weak. However, there was no direct correlation between PML and CBP expression in the NPC examined. In addition, there was low or no expression of Bax in the NP and NPC. This is, to our knowledge, the first report describing PML and CBP expression in NPC and our data strongly suggests that PML and CBP, but not Bax, may play a role in the transformed phenotypes of NPC.
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PMID:Differential expression of the suppressor PML and Ki-67 identifies three subtypes of human nasopharyngeal carcinoma. 1214 48


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