Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies

Linden, Michael A.; Kirchhof, Nicole; Carlson, Cathy S.; Ness, Brian G. Van

doi:10.1182/blood-2003-10-3399

Cited by 45 publications

(51 citation statements)

References 24 publications

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“…On the other hand, targeted overexpression of Bcl-xL and c-Myc in B-lymphoid cells in mice resulted in lymphoproliferative disease and plasma cell malignancies. These findings were evidence that Bcl-xL can contribute to plasmacytomagenesis [30]. Bcl-xL expression is also associated with drug resistance in MM patients [31].…”

Section: Bcl-2 Proteins Are Key Targets Of Therapeuticsmentioning

confidence: 82%

Apoptosis of Multiple Myeloma

Oancea

Mani²,

Hussein³

et al. 2004

International Journal of Hematology

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Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. MM cells localize to the bone marrow, where cell adhesion-mediated autocrine or paracrine activation of various cytokines, such as interleukin 6, insulin-like growth factor 1, and interferon α, results in their accumulation mainly because of loss of critical apoptotic controls. Resistance to apoptosis, a genetically regulated cell death process, may play a critical role in both pathogenesis and resistance to treatment of MM. Abnormalities in regulation and execution of apoptosis can contribute to tumor initiation, progression, as well as to tumor resistance to various therapeutic agents. Apoptosis is executed via 2 main pathways that lead to activation of caspases: the death receptor (extrinsic) pathway and the mitochondrial (intrinsic) pathway. Ionizing radiation and chemotherapeutic agents act primarily through the intrinsic pathway, in which mitochondria play the central role. Various therapeutic modalities that are effective in MM modulate levels of the proapoptotic and antiapoptotic Bcl-2 family of proteins and of inhibitors of apoptosis, expression of which is primarily regulated by p53, nuclear factor κB, and STAT (signal transducers and activators of transcription) factors. This review focuses on the key concepts and some of the most recent studies of signaling pathways regulated in MM and summarizes what is known about the clinical role of these pathways.

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Section: Bcl-2 Proteins Are Key Targets Of Therapeuticsmentioning

confidence: 82%

Apoptosis of Multiple Myeloma

Oancea

Mani²,

Hussein³

et al. 2004

International Journal of Hematology

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“…3 'Survival gene' Bcl-xl was reported to be critical in DC survival and in the magnitude of generated immune responses. 17,19 Owing to the possibilities of apoptosis of antigen-bearing somatic cells presentation to CD8+ T cells by local DCs and Bcl-xl-induced tumorgensis, [21][22][23]25 prolonging specifically DC survival in vivo may be an attractive strategy to improve T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, overexpression of Bcl-xl may contribute to tumorgensis in vivo. 25 This raises the concern that delivery of Bcl-xl DNA in vivo into somatic cells, B cells and stem cells may induce tumorgensis. Expressing Bclxl under control of the DC-specific (CD11c) promoter 26 would specifically prolong the lifespan of DCs without interfering with antigen-bearing somatic cells dying (an antigen resource for DCs), but at the same time may minimize the incidences of Bcl-xl-induced tumorgensis (due to the related short life, nonproliferation and terminal differentiation of DCs in vivo).…”

Section: Introductionmentioning

confidence: 99%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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T-cell priming is strongly affected by the longevity of antigenbearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. 'Survival gene' Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFNg-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that 'survival gene' Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer. Gene Therapy (2005) 12, 1517-1525.

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“…15 Transgenic mice overexpressing a Bcl-xL transgene in mature B cells and plasma cells develop nonmalignant accumulation of plasma cells, whereas coexpression of Bcl-xL and c-Myc leads to development of aggressive plasma cell malignancies. 16 Together, these findings raise the possibility that inhibition of Bcl-2 family protein function may abrogate the survival effect that is bestowed upon MM cells by antiapoptotic molecules and elicit programmed cell death of the malignant plasma cells.…”

Section: Introductionmentioning

confidence: 98%