The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo

Mi Ae Lyu, Deepak Rai, Kwang Seok Ahn, Bokyung Sung, Lawrence H. Cheung, John W. Marks, Bharat B. Aggarwal, Ricardo C T Aguiar, Varsha Gandhi, Michael G. Rosenblum

Research output: Contribution to journalArticle

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) and accounts for 30% to 40% of NHL. Molecules targeting nuclear factor-κB (NF-κB) are expected to be of therapeutic value in those tumors where NF-κB seems to play a unique survival role such as activated B-cell (ABC)-subtype DLBCL. We previously generated a rGel/BLyS fusion toxin for receptor-mediated delivery of the rGel toxin specifically to malignant B cells. In this study, we examined this fusion toxin for its ability to suppress DLBCL growth in vitro and in vivo. rGel/BLyS was specifically cytotoxic to DLBCL lines expressing all three BLyS receptors and constitutively active NF-κB. Treatment with rGel/BLyS induced down-regulation of the phosphorylation of inhibitory subunit of NF-κB (IκB-α), inhibition of NF-κB DNA-binding activity, and accumulation of IκB-α. In agreement with these results, we additionally found that rGel/BLyS downregulated levels of several NF-κB targets including Bcl-xL, Mcl-1, survivin, and x-chromosome linked inhibitor-of-apoptosis. Treatment also induced up-regulation of Bax and apoptosis through caspase-3 activation and poly ADP-ribose polymerase cleavage. Importantly, rGel/BLyS significantly inhibited tumor growth (P < .05) in a DLBCL xenograft model. Thus, our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive NHLs that are both dependent on NF-κB and are resistant to conventional chemotherapeutic regimens.

Original languageEnglish (US)
Pages (from-to)366-375
Number of pages10
JournalNeoplasia
Volume12
Issue number5
DOIs
StatePublished - May 2010

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Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Growth
Non-Hodgkin's Lymphoma
Down-Regulation
Apoptosis
Poly(ADP-ribose) Polymerases
B-Cell Lymphoma
Heterografts
Caspase 3
Neoplasms
Up-Regulation
Chromosomes
Phosphorylation
Cell Line
In Vitro Techniques
rGel-BLyS fusion toxin
DNA
Therapeutics

ASJC Scopus subject areas

  • Cancer Research

Cite this

Lyu, M. A., Rai, D., Ahn, K. S., Sung, B., Cheung, L. H., Marks, J. W., ... Rosenblum, M. G. (2010). The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. Neoplasia, 12(5), 366-375. https://doi.org/10.1593/neo.91960

The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. / Lyu, Mi Ae; Rai, Deepak; Ahn, Kwang Seok; Sung, Bokyung; Cheung, Lawrence H.; Marks, John W.; Aggarwal, Bharat B.; Aguiar, Ricardo C T; Gandhi, Varsha; Rosenblum, Michael G.

In: Neoplasia, Vol. 12, No. 5, 05.2010, p. 366-375.

Research output: Contribution to journalArticle

Lyu, MA, Rai, D, Ahn, KS, Sung, B, Cheung, LH, Marks, JW, Aggarwal, BB, Aguiar, RCT, Gandhi, V & Rosenblum, MG 2010, 'The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo', Neoplasia, vol. 12, no. 5, pp. 366-375. https://doi.org/10.1593/neo.91960
Lyu, Mi Ae ; Rai, Deepak ; Ahn, Kwang Seok ; Sung, Bokyung ; Cheung, Lawrence H. ; Marks, John W. ; Aggarwal, Bharat B. ; Aguiar, Ricardo C T ; Gandhi, Varsha ; Rosenblum, Michael G. / The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. In: Neoplasia. 2010 ; Vol. 12, No. 5. pp. 366-375.
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