Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor κB

Nishioka, Chie; Ikezoe, Takayuki; Yang, Jing; Komatsu, Naoki; Bandobashi, Kentaro; Taniguchi, Ayuko; Kuwayama, Yoshio; Togitani, Kazuto; Koeffler, H. Phillip; Taguchi, Hirokuni

doi:10.1016/j.leukres.2007.05.026

Cited by 50 publications

(46 citation statements)

References 23 publications

(26 reference statements)

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“…This finding is also consistent with a model of thrombocytopenia involving temporary disruption of nuclear factor-kB signaling, as the NFkB transcription factor is important in megakaryocyte maturation, 8 and panobinostat is known to block nuclear translocation of NFkB. 6 A study by Matsuoka et al 12 also found that megakaryocyte numbers in rat spleen increase in response to the histone deacetylase inhibitor FR235225, and that inhibition of GATA-1 in megakaryocytes is associated with histone deacetylase inhibitor-induced thrombocytopenia. Thus, our data show that megakaryocytes are neither lost nor undergo prolonged morphological changes because of therapy, and that enhanced megakaryocytopoiesis ensues following induction of thrombocytopenia.…”

supporting

confidence: 76%

“…The mechanisms of bortezomib-and panobinostat-induced thrombocytopenia are not well understood, but both may involve effects on nuclear factor-kB (NFkB) nuclear translocation and downstream gene targets. [6][7][8] Here, we evaluated the kinetics of thrombocytopenia and the fate of BM megakaryocytes in panobinostat-treated mice. We hypothesized that the rate of blood platelet reduction would reflect a panobinostat-induced cessation of platelet production, rather than megakaryocyte loss, and that platelet generation by megakaryocytes would resume on discontinuation of panobinostat treatment.…”

mentioning

confidence: 99%

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Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

et al. 2010

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supporting

confidence: 76%

mentioning

confidence: 99%

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

et al. 2010

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“…49 Moreover, in a murine model of human ATL, 50 HDAC inhibitors are able to trigger growth arrest and death of HTLV-1-infected cell lines and ATL cells via activation of the death-receptor pathway and potentialization of tumor necrosis factor-related apoptosis-inducing ligand response. 51 More generally, epigenetic drugs are known to regulate expression of tumor-suppressor genes and activities of transcriptional factors involved in cancer initiation and progression. In the HTLV-1 model of leukemogenesis, HBZ is critical for immune escape and proliferation of ATL cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Belrose

Gross

Olindo

et al. 2011

Blood

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IntroductionHuman T-lymphotropic virus-1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). 1,2 Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (ACs), the lifetime cumulative risk of developing ATL or HAM/ TSP is Ͻ 5%. HTLV-1-provirus integrates into the genome of infected cells, predominantly CD4 ϩ CD25 ϩ T lymphocytes, which represent the main reservoir in peripheral blood. 3 HAM/TSP, a central nervous system neuroinflammatory disease, is associated with perivascular and parenchymal infiltration of HTLV-1-infected T cells and activated cytotoxic T lymphocytes (CTLs). 4 A major determinant of HAM/TSP development is the HTLV-1-infected cell burden. The peripheral blood HTLV-1-proviral load is higher in HAM/TSP patients than AC. 5,6 Follow-up studies of HAM/TSP cohorts showed that high provirus loads were associated with rapid disease progression. [7][8][9] Those studies also demonstrated a relative stability of the HTLV-1-proviral load throughout the disease. Set-point provirus load and subsequent HAM/TSP risk are influenced by the cellular immune-response efficiency, 10 although excessive activation of HTLV-1-specific CTLs might become deleterious and contribute to central nervous system tissue damage. 4 Host-pathogen interplay is characterized by very dynamic kinetics, resulting in an equilibrium between the virus-driven clonal expansion of infected T cells 11 and tight control exerted by the immune response. 10 Tax, a transactivator protein encoded by the pX region of the HTLV-1 genome, plays a central role in disease pathogenesis. Tax activates viral transcription and also modulates many cellular signaling pathways involved in T cell activation, cycling, apoptosis or a combination. 12 Tax expression is promitotic and drives CD4 ϩ T-cell proliferation. 13 At the same time, Tax is the immunodominant target recognized by the CTL response. 14 Rapid immune elimination of Tax-expressing cells may explain the poor detection of Tax-gene products (ie, mRNA or protein) in freshly isolated peripheral blood mononuclear cells (PBMCs) from infected patients. 15-18 Short-term culture enables Tax detection and ex vivo conditions might allow Tax-expressing cells to escape immune selective pressure. 19 The current model of HTLV-1 accumulation and persistence supposes 2 steps: first, Tax expression propels CD4 ϩ T cells into cell cycling, which is well documented; and second, silencing of virus expression allows escape from immune surveillance, which remains to be elucidated. Epigenetic mechanisms might participate in silencing of HTLV-1 gene transcription. 20 Use of histone deacetylase (HDAC) inhibitors, such as valproate (2-npropylpentanoic acid, VPA), was postulated to transiently activate virus expression and thereby expose the latent virus reservoir to immune destruction. 21,22 Another avenue of research focuses on negative posttranscriptional regulators of virus expression, eg, pX-encoded Rex and p30 II...

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“…32 We have recently shown that MS-275 inhibited the nuclear factor kB, which stimulated a variety of antiapoptotic molecules, such as bcl-2 family members, and induced growth arrest and apoptosis of adult T-cell leukemia cells. 8 We have recently shown that SAHA (vorinostat), one of the HDACI derived from hydroxamic acid, also inhibited Akt/mTOR signaling, resulting in the downregulation of cyclin D1 in mantle cell lymphoma cells. 33 In addition, other investigators found that SAHA as well as tricostatin A inhibited Akt activity in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…6 For example, we previously showed that SAHA and MS-275 induced growth arrest and apoptosis of human mantle cell lymphoma and adult T-cell leukemia cells, respectively, in association with the induction of histone acetylation of the p21 waf1 promoter region, resulting in the upregulation of p21 waf1 protein. 7,8 Promyelocytic leukemia/retinoic acid (RA) receptor-a fusion protein, generated by chromosomal translocation in acute promyelocytic leukemia (APL) recruits HDAC and repressor complexes on RA target promoters and silences RA signaling, resulting in the differentiation block of hematopoietic stem cells. 9 RA, at pharmacological concentration, dissociates HDAC and repressor complexes and recruits coactivators to the promoter and activates RA signaling, resulting in terminal differentiation.…”

Section: Introductionmentioning

confidence: 99%

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

et al. 2008

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This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K by western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analog RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27 kip1 and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by the expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce the expression of the myeloid differentiation-related transcription factor, CCAAT enhancer-binding protein-e, in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of an HDACI and an mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.

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Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor κB

Abstract: Abbreviations: ATL, adult T-cell leukemia; HTLV-1, human T-cell lymphotropic virus type I; HDACIs, histone deacetylase inhibitors; SAHA, suberoylanilide hydroxamic acid; NF-κB, nuclear factor kappa B; IκBα, inhibitory subunit of NF-κB; XIAP, X-linked inhibitor of apoptosis protein.

Cited by 50 publications

References 23 publications

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

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