scholarly journals Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256320
Author(s):  
Yanuar Rahmat Fauzi ◽  
Shingo Nakahata ◽  
Syahrul Chilmi ◽  
Tomonaga Ichikawa ◽  
Phawut Nueangphuet ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Dependent Manner ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Xenograft Mouse Model ◽  
Adult T Cell Leukemia ◽  
Atll Cell

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.

The Overexpression of Enhancer of Zeste Homologue 2 Is Associated with Tumor Proliferation and Aggressive Behavior in Adult T-Cell Leukemia/Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3959-3959
Author(s):  
Daisuke Sasaki ◽  
Yoshitaka Imaizumi ◽  
Hiroo Hasegawa ◽  
Akemi Osaka ◽  
Kazuto Tsuruda ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Cell Lines ◽  
Western Blotting ◽  
Acute Type ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Atll Cell ◽  
Enhancer Of Zeste

Abstract Abstract 3959 Poster Board III-895 Background Enhancer of zeste homologue 2 (EZH2) is a critical component of the Polycomb Repressive Complexes PRC2, which mediates epigenetic gene silencing by the trimethylation of Lys27 of histone 3 (H3K27). This regulation is not only involved in embryonic development and stem cell renewal, but also in tumor progression. Adult T-cell leukemia/lymphoma (ATLL) is a single disease entity etiologically associated with human T-cell leukemia virus type-1 (HTLV-1). Its clinical behavior, however, is quite diverse among patients and is thus subclassified into several subtypes. The prognosis of the aggressive subtypes is very poor based on standard chemotherapy, and so the development of a new therapeutic approach is urgent. Results In a comparative microarray analysis of primary ATLL samples, the acute type showed significantly higher EZH2, YY1, and RYBP (RING1 and YY1 binding protein) expressions compared with the chronic type. Further analysis employing real-time quantitative RT-PCR of various Polycomb group (PcG)-related proteins, including the ones mentioned above, revealed that the mRNAs of two other PRC2 components, EED and RBBP4, were also significantly elevated in ATLL, irrespective of the subtypes, compared with lymphocytes from HTLV-1 carriers. These results suggest that the dysregulation of PRC2 is a key event in the development and progression of ATLL. In the immunohistochemical analysis of ATLL lymph nodes, the nuclei of over 90% of ATLL cells were positive for EZH2, which in clear contrast to reactive or indolent B-lymphoma lymph nodes in which a few cells were positive. It has been shown that activated Akt phosphorylates EZH2 at serine 21 and suppresses its methyltransferase activity. Western blotting of EZH2 showed that EZH2 of primary ATLL cells was not phospholyrated and remained in its active form. Indeed, the trimethylation of H3K27 in ATLL cells was confirmed by Western blotting and immunohistochemistry, whereas it was completely absent in lymphocytes from HTLV-1 carriers. Finally, in studies using ATLL cell lines, the knockdown of EZH2 by siRNA caused decrease in cell proliferation. Moreover, ATLL cell lines showed high sensitivities to histone deacetylase (HDAC) inhibitors as LBH589, and LBH589 decreased EZH2 expression. EZH2 inhibitor 3-deazaneplancin A (DZNeP) also reduced cell growth, not only in primary ATLL cells, but also in ATLL cells lines. These results strongly support the rationale for developing molecular targeting therapies against EZH2 in ATLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5163-5172 ◽  
Author(s):  
Jing Chen ◽  
Mike Petrus ◽  
Bonita R. Bryant ◽  
Vinh Phuc Nguyen ◽  
Mindy Stamer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Proximal Promoter ◽  
Type I ◽  
Dependent Manner ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Spontaneous Proliferation

AbstractThe etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.

Frequent expression of interleukin-9 mRNA and infrequent involvement of interleukin-9 in proliferation of primary adult T-cell leukemia cells and HTLV-I infected T-cell lines

1997 ◽  
Vol 21 (3) ◽  
pp. 211-216 ◽  
Author(s):  
Kakushi Matsushita ◽  
Naomichi Arima ◽  
Hideo Ohtsubo ◽  
Hiroshi Fujiwara ◽  
Shiroh Hidaka ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
T Cell Lines ◽  
Interleukin 9

scholarly journals Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone

2019 ◽  
Vol 19 ◽  
pp. 100257 ◽  
Author(s):  
Nicole A. Kohart ◽  
Said M. Elshafae ◽  
Wachirapan Supsahvad ◽  
Aylin Alasonyalilar-Demirer ◽  
Amanda R. Panfil ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Phenotypic Heterogeneity ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human Adult

Response: Estimating frequency of cancer stem cells in a mouse model of adult T-cell leukemia/lymphoma

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2118-2118
Author(s):  
Jumpei Yamazaki ◽  
Takuo Mizukami ◽  
William W. Hall ◽  
Isao Hamaguchi
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cancer Stem Cells ◽  
Mouse Model ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma

2007 ◽  
Vol 67 (24) ◽  
pp. 11859-11866 ◽  
Author(s):  
S. T. Shu ◽  
M. V.P. Nadella ◽  
W. P. Dirksen ◽  
S. A. Fernandez ◽  
N. K. Thudi ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Effective Therapy ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

Anti-Adult T-Cell Leukemia Effects of a Novel Synthetic Retinoid, Am80 (Tamibarotene) through Inhibition of NF-κB.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2525-2525
Author(s):  
Tetsuro Nakazato ◽  
Chie Ishikawa ◽  
Taeko Okudaira ◽  
Mariko Tomita ◽  
Naoki Mori
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
T Cell ◽  
Cell Lines ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Synthetic Retinoid ◽  
T Cell Lines

Abstract Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. Retinoid is a collective term for compounds, which bind to and activate retinoic acid receptors (RARα, β, γ and RXRα, β, γ), members of nuclear hormone receptor superfamily. It is involved in cell differentiation, morphogenesis, proliferation, and anti-neoplastic processes. The most important endogenous retinoid is all-trans-retinoic acid (ATRA), which is an RARα, β, and γ ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and adult T-cell leukemia (ATL). Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific (but RARγ- and RXRs-nonbinding) synthetic retinoid that is expected to overcome ATRA resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein. On this background, we examined the inhibitory effect of Am80 on HTLV-I-infected T-cell lines and primary ATL cells. Am80 showed little growth inhibition of peripheral blood mononuclear cells, but it markedly inhibited the growth of both HTLV-I-infected T-cell lines and primary ATL cells. Am 80 could arrest cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. The NF-κB pathway is critical for the immortalization and survival of HTLV-I-infected T cells. Therefore, NF-κB pathway was examined as potential targets of Am80 signaling. Am80 significantly inhibited phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with the reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Furthermore, in animal studies, treatment with Am80 produced partial inhibition of growth of tumors of an HTLV-I-infected T-cell line transplanted subcutaneously in severe combined immunodeficient mice. These findings clearly demonstrate that Am80 is a potential inhibitor of NF-κB in ATL cells, and might be a useful therapeutic agent against ATL.

Cell Cycle Deregulation Determines Acute Transformation In Chronic Type Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 845-845
Author(s):  
Noriaki Yoshida ◽  
Kennosuke Karube ◽  
Atae Utsunomiya ◽  
Kunihiro Tsukasaki ◽  
Yoshitaka Imaizumi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Lines ◽  
P Value ◽  
Acute Type ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Chronic Type ◽  
Adult T Cell Leukemia ◽  
Oligo Array

Abstract Introduction Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes; acute, lymphoma, chronic and smoldering. Although chronic and smoldering subtypes are regarded as indolent ATL, about half of these cases progress to acute type ATL and subsequent death. Therefore, cases of indolent ATL also have poor prognosis and acute transformation is a predictive indicator for patients with indolent ATL. However, the molecular pathogenesis of acute transformation remains unknown. In the present study, oligo-array comparative genomic hybridization (CGH) and comprehensive gene-expression profiling (GEP) were applied to 27 and 35 cases of chronic and acute type ATL, respectively, in an effort to delineate the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation. Materials and Methods All DNA and RNA used in this study were extracted from purified CD4-positive cells. Oligo-array CGH analyses and comprehensive GEP analyses were performed on 27 and 35 cases of chronic and acute type ATL, respectively. Subsequently, we established Tet-OFF ATL cell lines for functional analyses. Results Oligo-array CGH revealed that genomic loss of 9p21.3 was significantly characteristic of acute type ATL, but not chronic type ATL (p-value= 0.039). Although the minimal common deleted region of 9p21.3 contained MTAP, CDKN2A and CDKN2B, the expression level of only CDKN2A was reduced with genomic loss of 9p21.3 (Figure 1). Moreover, analysis of serial samples of a chronic type ATL patient showing acute transformation also revealed that reduction of CDKN2A expression by 9p21.3 loss was associated with acute transformation in this case. CDKN2A contains two known variants, INK4a and ARF. Re-expression of INK4a and ARF suppressed proliferation of Tet-OFF ATL cell lines, while the suppression efficiency of INK4a was stronger than that of ARF (Figure 2). In cell-cycle assays, the induction of INK4a and ARF decreased the proportion of S-phase cells. Additionally, re-expression of INK4a also increased the amount of apoptotic cells in induced cell lines, while re-expression of ARF did not have this effect. Since CDKN2A is a well-known cell cycle regulator, deregulation of the cell-cycle might be involved in acute transformation of chronic type ATL. In fact, deregulation of the cell-cycle pathway has been reported as a predictive indicator for the outcome in diffuse large B-cell lymphoma patients (Cancer Cell, 22:359-372). Therefore, we examined whether chronic ATL patients had alterations in cell-cycle related genes and found that chronic ATL patients could be divided into two groups. The group possessing alterations in these genes (referred to as “Cell cycle Alteration”) showed poorer prognosis compared with the group lacking such alterations (referred to as “Clean”) (p-value= 0.037) (Figure 3). Additionally, patients with such alterations tended to have earlier progression to acute type ATL. Conclusion These findings indicated that cell cycle-related genes play an important role in acute transformation and should serve as good prognostic markers for chronic type ATL. Disclosures: No relevant conflicts of interest to declare.

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