News and Commentary
Published: 22 April 2005

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

Y Kfoury¹,
R Nasr¹,
O Hermine²,
H de Thé³ &
…
A Bazarbachi¹

Cell Death & Differentiation volume 12, pages 871–877 (2005)Cite this article

1398 Accesses
37 Citations
Metrics details

Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of activated T cells resistant to chemotherapy. The viral transactivator protein Tax is responsible for several aspects of the malignant transformation such as proliferation, resistance to apoptosis, genetic instability, tumor dissemination, immune escape and chemotherapy resistance. Through all of these activities, Tax acts as a powerful oncogene and represents the most attractive viral protein for targeted therapy. Among Tax properties, activation of the NF-κB pathway plays a crucial role in the proliferation and transformation of the infected cells. Indeed, most of the activated cellular genes in HTLV-I-infected cells are through this mechanism. In this review, we summarized the molecular mechanisms of Tax-induced NF-κB activation. We then presented the effect, and mechanism of action, of new potential treatment modalities targeting Tax and/or the NF-κB pathway, including arsenic trioxide, interferon alpha and proteasome inhibitors.

The HTLV-I is the causative agent of adult ATL¹ and of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). ² ATL is an aggressive lymphoproliferative disorder³ characterized by the proliferation of constitutively activated CD4+ T cells with convoluted nuclei and basophilic cytoplasm. The serum of ATL patients contains antibodies against HTLV-I¹ and the HTLV-I provirus is clonally integrated in the ATL cells. The disease occurs in native individuals from the HTLV-I endemic regions (i.e. the southern Japan, the Carribean, intertropical Africa, Brazil and northern Iran).⁴ Although HTLV-I can be transmitted intravenously or through sexual intercourse, vertical transmission through breast-feeding is required for ATL development. Out of the 10–20 million people who are infected with HTLV-I worldwide, only 3–10% develop ATL after a latent period of infection.

References

Hinuma Y (1982) Gan. To Kagaku Ryoho 8: 1313–1320
Gessain A et al. (1985) Lancet 2: 407–410
Bazarbachi A and Hermine O (2001) Virus Res. 78: 79–92
Gessain A and de The G (1996) Adv. Virus Res. 47: 377–426
Bazarbachi A et al. (2004) Lancet Oncol. 5: 664–672
Mortreux F et al. (2003) Leukemia 17: 26–38
Burton M et al. (2000) J. Virol. 74: 2351–2364
Yoshida M (2001) Annu. Rev. Immunol. 19: 475–496
Waldmann TA et al. (1993) Blood 82: 1701–1712
Suzuki T et al. (1999) Virology 259: 384–391
Jeang KT et al. (2004) J. Biol. Chem. 279: 31991–31994
Neuveut C et al. (1998) Mol. Cell Biol. 18: 3620–3632
Jeang KT et al. (1990) Science 247: 1082–1084
Gabet AS et al. (2003) Oncogene 22: 3734–3741
Mori N et al. (2001) Virus Genes 22: 279–287
Brauweiler A et al. (1997) Virology 231: 135–140
Kawakami A et al. (1999) Blood 94: 3847–3854
Mahieux R et al. (2000) AIDS Res. Hum. Retroviruses 16: 1677–1681
Pise-Masison CA et al. (2000) AIDS Res. Hum. Retroviruses 16: 1669–1675
Mesnard JM and Devaux C (1999) Virology 257: 277–284
Arnulf B et al. (2002) Blood 100: 4129–4138
El-Sabban ME et al. (2002) Blood 99: 3383–3389
Bazarbachi A (2004) Cancer Res. 64: 2039–2046
Grassmann R et al. (1989) Proc. Natl. Acad. Sci. USA 86: 3351–3355
Tanaka A et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1071–1075
Nerenberg M et al. (1987) Science 237: 1324–1329
Sun SC and Xiao G (2003) Cancer Metastasis Rev. 22: 405–422
Baldwin Jr. AS (1996) Annu. Rev. Immunol. 14: 649–683
Baeuerle PA and Henkel T (1994) Annu. Rev. Immunol. 12: 141–179
Ryseck RP et al. (1992) Mol. Cell Biol. 12: 674–684
Zabel U and Baeuerle PA (1990) Cell 61: 255–265
Whiteside ST et al. (1997) EMBO J. 16: 1413–1426
Inoue J et al. (1992) Cell 68: 1109–1120
Verma IM et al. (1995) Genes Dev. 9: 2723–2735
Henkel T et al. (1992) Cell 68: 1121–1133
Nolan GP et al. (1993) Mol. Cell Biol. 13: 3557–3566
Caamano JH et al. (1996) Mol. Cell Biol. 16: 1342–1348
Pahl HL (1999) Oncogene 18: 6853–6866
Chen ZJ et al. (1996) Cell 84: 853–862
Yamaoka S et al. (1998) Cell 93: 1231–1240
Rothwarf DM et al. (1998) Nature 395: 297–300
Tojima Y et al. (2000) Nature 404: 778–782
Nakano H et al. (1998) Proc. Natl. Acad. Sci. USA 95: 3537–3542
Le Bail O et al. (1993) EMBO J. 12: 5043–5049
Mercurio F et al. (1993) Genes Dev. 7: 705–718
Palombella VJ et al. (1994) Cell 78: 773–785
Chu ZL et al. (1998) J. Biol. Chem. 273: 15891–15894
Sun SC et al. (1994) Mol. Cell Biol. 14: 7377–7384
Good L and Sun SC (1996) J. Virol. 70: 2730–2735
Harhaj EW and Sun SC (1998) J. Biol. Chem. 273: 25185–25190
Sun SC and Ballard DW (1999) Oncogene 18: 6948–6958
Xiao G and Sun SC (2000) Oncogene 19: 5198–5203
Huang GJ et al. (2002) FEBS Lett. 531: 494–498
Yin MJ et al. (1998) Cell 93: 875–884
Uhlik M et al. (1998) J. Biol. Chem. 273: 21132–21136
Prajapati S and Gaynor RB (2002) J. Biol. Chem. 277: 24331–24339
Fu DX et al. (2003) J. Biol. Chem. 278: 1487–1493
Xiao G et al (2001) EMBO J. 20: 6805–6815
Hirai H et al. (1992) Oncogene 7: 1737–1742
Rousset R et al. (1996) Nature 381: 328–331
Lanoix J et al. (1994) Oncogene 9: 841–852
Suzuki T et al. (1995) Oncogene 10: 1199–1207
Hirai H et al. (1994) Proc. Natl. Acad. Sci. USA 91: 3584–3588
Pepin N et al. (1994) Virology 204: 706–716
Suzuki T et al. (1994) Oncogene 9: 3099–3105
Bex F et al. (1997) J. Virol. 71: 3484–3497
Bex F et al. (1998) Mol. Cell Biol. 18: 2392–2405
Robek MD and Ratner L (1999) J. Virol. 73: 4856–4865
Portis T et al. (2001) Blood 98: 1200–1208
Ballard DW et al. (1988) Science 241: 1652–1655
Chen GQ et al. (1996) Blood 88: 1052–1061
Zhu J et al. (2001) Oncogene 20: 7257–7265
Bazarbachi A et al. (1999) Blood 93: 278–283
El-Sabban ME et al. (2000) Blood 96: 2849–2855
Nasr R et al. (2003) Blood 101: 4576–4582
Beraud C and Greene WC (1996) J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl 1): S76–S84
Hemelaar J et al. (2001) J. Virol. 75: 11106–11115
Lonard DM et al. (2000) Mol. Cell 5: 939–948
Boes B et al (1994) J. Exp. Med. 179: 901–909
Cascio P et al (2002) EMBO J. 21: 2636–2645
Lallemand-Breitenbach V et al. (2001) J. Exp. Med. 193: 1361–1371
Lomas ME et al. (2002) J. Gen. Virol. 83: 641–650
Bangham CR (2000) Curr. Opin. Immunol. 12: 397–402
Hermine O et al. (2004) Hematol. J. 5: 130–134
Mori N et al. (2002) Blood 100: 1828–1834
Dewan MZ et al. (2003) J. Virol. 77: 5286–5294
Adams J (2003) Cancer Treat Rev. 29 (Suppl 1): 3–9
Jentsch S and Schlenker S (1995) Cell 82: 881–884
Hershko A and Ciechanover A (1998) Annu. Rev. Biochem. 67: 425–479
Ciechanover A and Ben-Saadon R (2004) Trends Cell Biol. 14: 103–106
Thrower JS et al. (2000) EMBO J. 19: 94–102
Chiari E et al. (2004) J. Virol. 78: 11823–11832
Tan C and Waldmann TA (2002) Cancer Res. 62: 1083–1086
Mitra-Kaushik S et al. (2004) Blood 104: 802–809
Satou Y et al. (2004) Leukemia 18: 1357–1363
Nasr R et al. (2005) Oncogene 24: 419–430
Lau A et al. (1998) Blood 91: 2467–2474
Ikeda K et al. (1999) Int. J. Cancer 82: 599–604
Tamiya S et al. (1998) Blood 91: 3935–3942

Download references

Acknowledgements

This work was supported by the American University of Beirut University Research Board and Medical Practice Plan, the Lebanese National Council for Scientific Research, the Diana Tamari Sabbagh Foundation, the CNRS contrat PICS, ARECA, HERN, Cancéropole, the Eli Lilly International Foundation and the Lady TATA memorial trust.

Author information

Authors and Affiliations

Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
Y Kfoury, R Nasr & A Bazarbachi
CNRS UMR 8603 and Department of Hematology, Necker Hospital, Paris, France
O Hermine
UPR 9051 CNRS, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Paris, France
H de Thé

Authors

Y Kfoury
View author publications
Search author on:PubMed Google Scholar
R Nasr
View author publications
Search author on:PubMed Google Scholar
O Hermine
View author publications
Search author on:PubMed Google Scholar
H de Thé
View author publications
Search author on:PubMed Google Scholar
A Bazarbachi
View author publications
Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to H de Thé or A Bazarbachi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kfoury, Y., Nasr, R., Hermine, O. et al. Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway. Cell Death Differ 12 (Suppl 1), 871–877 (2005). https://doi.org/10.1038/sj.cdd.4401624

Download citation

Published: 22 April 2005
Issue date: 01 August 2005
DOI: https://doi.org/10.1038/sj.cdd.4401624

This article is cited by

Primary cells from patients with adult T cell leukemia/lymphoma depend on HTLV-1 Tax expression for NF-κB activation and survival
- Rita Hleihel
- Hala Skayneh
- Ali Bazarbachi
Blood Cancer Journal (2023)
The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1)
- Rita Hleihel
- Behzad Khoshnood
- Ali Bazarbachi
Retrovirology (2018)
Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer
- Kenneth Alibek
- Stephanie Irving
- Aizada Chinybayeva
Infectious Agents and Cancer (2014)
Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression
- A Mühleisen
- M Giaisi
- M Li-Weber
Cell Death & Disease (2014)
HTLV-1 Tax protein cooperates with Ras in protecting cells from apoptosis
- Nicola Vajente
- Roberta Trevisan
- Daniela Saggioro
Apoptosis (2009)

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

Log in or create a free account to read this content

References

Acknowledgements

Author information

Authors and Affiliations

Corresponding authors

Rights and permissions

About this article

Cite this article

This article is cited by

Primary cells from patients with adult T cell leukemia/lymphoma depend on HTLV-1 Tax expression for NF-κB activation and survival

The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1)

Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer

Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression

HTLV-1 Tax protein cooperates with Ras in protecting cells from apoptosis

Search

Quick links

Log in or create a free account to read this content

References

Acknowledgements

Author information

Authors and Affiliations

Corresponding authors

Rights and permissions

About this article

Cite this article

Share this article

This article is cited by

Primary cells from patients with adult T cell leukemia/lymphoma depend on HTLV-1 Tax expression for NF-κB activation and survival

The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1)

Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer

Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression

HTLV-1 Tax protein cooperates with Ras in protecting cells from apoptosis

Search

Quick links