Human T-cell lymphotropic-I-associated leukemia/lymphoma

Siegel, Robert; Gartenhaus, Ronald B.; Kuzel, Timothy M.

doi:10.1007/s11864-001-0022-8

Cited by 29 publications

(15 citation statements)

References 93 publications

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“…Recent reviews cite median survivals of less than 1 year despite advances in both chemotherapy and supportive care (Siegel et al, 2001). The 6 months median survival of Japanese patients with ATLL reported in Shimoyama's (1992) overview does not significantly differ from experience in Europe a decade later .…”

Section: Treatment Of Atllmentioning

confidence: 99%

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

2005

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After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-a plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naı¨ve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficultto-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

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Section: Treatment Of Atllmentioning

confidence: 99%

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

2005

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“…The HTLV-1 infection is endemic in southwestern Japan, Africa, the Caribbean Islands, and South America. The prognosis of patients with aggressive ATLL remains poor, with a median survival time of less than 1 year despite advances in both chemotherapy and supportive care (28,29,37). The viral determinant critical for the progression to T-cell malignancy in HTLV-1 carriers is thought to be the HTLV-1 transactivator/ oncoprotein Tax (1).…”

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confidence: 99%

Downregulation of CDKN1A in Adult T-Cell Leukemia/Lymphoma despite Overexpression of CDKN1A in Human T-Lymphotropic Virus 1-Infected Cell Lines

Watanabe¹,

Nakahata²,

Hamasaki³

et al. 2010

J Virol

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, and epigenetic abnormalities including promoter methylation are one of the mechanisms for the low CDKN1A expression in ATLL cells. Three HTLV-1-infected cell lines showed high levels of expression of both CDKN1A and Tax, but expression of CDKN1A was detected in only two of six ATLL-derived cell lines. In both the HTLV-1-infected and ATLL cell lines, we found that activated Akt phosphorylates CDKN1A at threonine 145 (T145), leading to cytoplasmic localization of CDKNIA. In HTLV-1-infected cell lines, cytoplasmic CDKN1A did not inhibit the cell cycle after UV irradiation; however, following treatment with LY294002, a PI3K inhibitor, CDKN1A was dephosphorylated and relocalized to the nucleus, resulting in suppression of the cell cycle. In the ATLL cell lines, treatment with LY294002 did not inhibit the cell cycle but induced apoptosis with the cytoplasmic localization. Therefore, the low CDKN1A expression in ATLL cells may be a key player in ATLL leukemogenesis, and the abnormal genomic methylation may influence the expression of not only HTLV-1 Tax but also CDKN1A during long-term development of ATLL from the HTLV-1-infected T lymphocytes.

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“…The vast majority of patients with ATL present with resistance to chemotherapy, limiting survival to less than a year. 5,6 Recent investigation of the molecular events associated with HTLV progression has identified a number of molecular targets within the virus and the host that could represent excellent targets for therapeutic intervention. The 40-kDa transactivator protein, Tax, mediates the transition from latency to virion production by interacting with specific host proteins associated with cellular transcriptional pathways such as nuclear factorB (NF-B), cyclic adenosine monophosphate response element-binding-activating transcription factor (CREB/ATF), serum response factor (SRF), stimulatory protein 1 (SP1), and early growth response protein 1 (EGR-1).…”

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confidence: 99%

Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants

Mitra-Kaushik

Harding

Hess

et al. 2004

Blood

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IntroductionHuman T-cell leukemia/lymphotropic virus type 1 (HTLV-1) infection is present in 10 to 20 million people worldwide. 1,2 HTLV-1 infection results in 2 different diseases: adult T-cell leukemia/lymphoma (ATLL or ATL) and the neurologic disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/ HAM). 3,4 Although the epidemiology and clinical characteristics of HTLV-1 infection are defined, the molecular mechanisms used by the virus to establish persistent infection and subsequently promote lymphocyte proliferation and the host immune evasion remain poorly understood. Thus, the quest for appropriate antiviral therapy and a vaccine are difficult, but important. The vast majority of patients with ATL present with resistance to chemotherapy, limiting survival to less than a year. 5,6 Recent investigation of the molecular events associated with HTLV progression has identified a number of molecular targets within the virus and the host that could represent excellent targets for therapeutic intervention. The 40-kDa transactivator protein, Tax, mediates the transition from latency to virion production by interacting with specific host proteins associated with cellular transcriptional pathways such as nuclear factorB (NF-B), cyclic adenosine monophosphate response element-binding-activating transcription factor (CREB/ATF), serum response factor (SRF), stimulatory protein 1 (SP1), and early growth response protein 1 (EGR-1). Through interaction with cellular transcription factors, Tax potently activates transcription from the viral promoter and enhancer elements of many cellular genes involved in host cell proliferation. 7,8 The oncogenic potential of Tax has been demonstrated in animal models, 9-12 and activation of NF-B has been implicated as a critical feature of transformation. 13,14 Tax may be responsible for many of the required events necessary for HTLV-1-mediated lymphocyte immortalization and transformation.The NF-B family of transcription factors participates in regulation of diverse biologic processes, including immune responses, cell growth, and apoptosis. [15][16][17][18][19] Mammalian cells express 5 NF-B members, RelA, RelB, c-Rel, p50, and p52, which function as various homodimers and heterodimers. 20 The NF-B factors are normally sequestered in the cytoplasm through physical interaction with ankyrin repeat-containing inhibitors, including IB␣ and related proteins. 21 A well-characterized pathway leading to NF-B activation is through phosphorylation and subsequent degradation of IB␣. 22,23 This canonical NF-B signaling pathway depends on a multisubunit IB kinase (IKK), which responds to various stimuli, such as the inflammatory cytokine tumor necrosis factor ␣ (TNF-␣), the mitogen phorbol 12-myristate 13-acetate (PMA), and certain viral proteins. 15,24,25 IKK is composed of 2 catalytic subunits, IKK␣ and IKK␤, and a regulatory subunit, IKK␥ (also named NEMO, IKKAP1,. 26 Another level of NF-B regulation is via processing of the NF-B1 and NF-B2 precursor proteins p105 and p100, a prot...

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Human T-cell lymphotropic-I-associated leukemia/lymphoma

Cited by 29 publications

References 93 publications

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

Downregulation of CDKN1A in Adult T-Cell Leukemia/Lymphoma despite Overexpression of CDKN1A in Human T-Lymphotropic Virus 1-Infected Cell Lines

Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants

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