Fas Gene Mutation in the Progression of Adult T Cell Leukemia

Maeda, Takahiro; Yamada, Yasuaki; Moriuchi, Ryozo; Sugahara, Kazuyuki; Tsuruda, Kazuto; Joh, T; Atogami, Sunao; Tsukasaki, Kunihiro; Tomonaga, Masao; Kamihira, Shimeru

doi:10.1084/jem.189.7.1063

Cited by 116 publications

(50 citation statements)

References 54 publications

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“…In contrast, it has been shown that induction of Tax expression was associated with a remarkable upregulation of Fas-ligand at the transcriptional level [Chen et al, 1997]. Nevertheless, the production of Fasligand by cells infected with HTLV-1 in vitro Maeda et al [1999]; in our experimental system was very low. Thus, it is highly improbable that the Fas/Fas-ligand system could be an upstream signal for the apoptotic pathway of infected cells in our HTLV-1-infected cultures.…”

Section: Discussioncontrasting

confidence: 67%

“…In particular, it was shown that resistance to Fas-mediated apoptosis in HTLV-1-infected cell lines might be dependent on the failure of Fas receptor clustering and caspase-8 activation, and that this could be overcome by treatment with cycloheximide [Kongphanich et al, 2002]. In addition Fas resistance in HTLV-1-transformed cells has been proposed to be irreversible owing to mutations in Fas-encoding genes, based on results obtained in a few adult T-cell leukemia/lymphoma cell lines [Tamya et al, 1998;Maeda et al, 1999]. This latter aspect might also be associated with a poor response to anticancer drugs [Tamya et al, 1998].…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have shown that resistance to apoptosis in HTLV-1-infected leukemic cells may be due to autocrine antiapoptotic signaling provided by over-expression of chemokines [Ruckes et al, 2001]. Nevertheless, it has been reported that adult T-cell leukemia/lymphoma cells, which express Fas antigen, retain a certain susceptibility to Fas-mediated apoptosis [Maeda et al, 1999]. Taken together these data indicate that in adult T-cell leukemia/lymphoma patients, leukemogenesis is associated to a rescue of host cells from death.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Matteucci

Balestrieri

Macchi

et al. 2004

Journal of Medical Virology

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Suppression of apoptosis has been proposed as a mechanism involved in the transforming action of human T-cell leukemia/lymphotropic virus type-1 (HTLV-1). However, there is evidence that HTLV-1 and its protein Tax also induce apoptosis. To resolve this apparent paradox, apoptosis was monitored in primary cultures of peripheral blood lymphocytes (PBLs) from healthy donors, following HTLV-1 infection in vitro. High levels of apoptosis in HTLV-1 infected cultures during the first weeks after infection were detected. Apoptosis was not related to the presence of uninfected cells, as revealed by a fluorescence in situ hybridization assay. Successively, a progressive decrease in apoptosis in infected cultures going towards immortalization, was observed. When IL-2 in the medium was replaced by IL-4, allowing the cells to be efficiently infected by HTLV-1 but not immortalized, apoptosis levels tended to increase, instead of decreasing, with the ongoing time. The caspase cascade was remarkably activated in PBLs recently infected in vitro by HTLV-1, but apoptosis was only partly reduced by caspase inhibitors. Even if spontaneous apoptosis was relatively low in long-term cultures of PBLs immortalized by HTLV-1 in vitro, Fas death-receptor expression and function were well conserved. These observations provide a new rationale for explaining the dual effect of HTLV-1 in controlling apoptosis.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Matteucci

Balestrieri

Macchi

et al. 2004

Journal of Medical Virology

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“…32 Several Fas gene mutations have also been described in lymphoid malignancies, including myelomas, 33 T cell lymphoblastic leukemias 34 and HTLV-I-related adult T cell leukemias (ATL). 35 In this latter disease, mutated Fas was also demonstrated to behave as a dominant-negative mutant, 36 which could account for the chemoresistance of ATL. Caspase-10 mutations, that account for some congenital ALPS without Fas mutation, 37 have not been so far identified in human lymphoid tumors.…”

Section: Leukemiamentioning

confidence: 99%

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

et al. 2000

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Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti-and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NF B transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.

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“…Their primary ATL cell origin was confirmed previously by the concordance of the integration site(s) of HTLV-I proviral DNA and/or the rearrangement profile of the T cell receptor (TCR) ␤-chain gene. [22][23][24][25] The MTAP gene consists of eight exons. 26 SO4 and ST1 have lost exons 5 to 8 and KK1 has lost all exons.…”

Section: Primary Atl Cells and Atl Cell Linesmentioning

confidence: 99%

Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL)

et al. 2002

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Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAPnegative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5Ј-deoxyadenosine, however, also caused the undesirable rescue of MTAPnegative ATL cell lines. 5Ј-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5Ј-deoxyadenosine rescue in MTAP-deficient ATL.

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Fas Gene Mutation in the Progression of Adult T Cell Leukemia

Cited by 116 publications

References 54 publications

Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL)

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