Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia

Schliep, Stefan; Decker, Thomas; Schneller, Folker; Wagner, Hermann; Häcker, Georg

doi:10.1016/j.exphem.2004.03.006

Cited by 21 publications

(18 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the presence of XIAP in CLL cells and its upregulation in conditions where apoptosis is prevented, no caspase-inhibiting effect of IAP has been detected. 26 This phenomenon might be partly explained by the uniformly strong expression of Smac/DIABLO in CLL cells, confirmed in the present study, possibly sufficient to overcome the caspase-inhibiting effect of IAPs. 26 This hypothesis is supported by the fact that the expression of Smac/DIABLO was lower in CD19 þ -B-cells as compared to CLL (Figure 2f).…”

Section: Resultssupporting

confidence: 69%

Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL)

et al. 2005

View full text Add to dashboard Cite

The pathogenic role of trisomy 12 in chronic lymphocytic leukemia (CLL) remains unresolved, but recently an upregulated RNA expression level has been observed for chromosome 12 candidate genes. In the current study, the protein expression of chromosome 12 candidate genes was characterized by comparing CLL cases with (n ¼ 58) or without (n ¼ 16) trisomy 12, CD19 þ -B-cells and cell lines (JVM-2, EHEB, JURKAT). Immunoblotting was performed to quantify the levels of AID, APAF-1, ARF3, CCND2, CDK2, CKD4, GLI, MDM-2, p27, Smac/ DIABLO and STAT6 (signal transducer and activator of transcription 6). The cell lines showed distinct expression patterns for CCND2, MDM-2, p27, Smac/DIABLO and STAT6, and displayed higher levels of CDK2 and CDK4 than the CLL cases. JURKAT and the CLL cases expressed uniformly high levels of p27, but low levels of CCND2. AID expression in the CLL cases was weak with slight variations regardless of the subgroup affiliation. The expression of the investigated proteins was independent of the trisomy 12 status as well as of the VH mutation status. The comparison of CD19 þ -B-cells with CLL revealed higher protein levels in CLL for CDK4, p27, Smac/ DIABLO and STAT6. Further studies including protein expression experiments in genetic high-risk subgroups of CLL have to elucidate whether these proteins qualify as candidates for targeted CLL therapies.

show abstract

Section: Resultssupporting

confidence: 69%

Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL)

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Nevertheless, the IgVH mutation status may serve as a biomarker to predict the responsiveness of CLL patients toward the combination therapy with XIAP inhibitor and TRAIL, a hypothesis to be confirmed in a larger group of CLL patients. High expression of XIAP has previously been reported in CLL, possibly as part of a NF-κB-regulated survival program (20)(21)(22). In addition, XIAP has recently been implicated in apoptosis resistance that is imposed by constitutively activated Notch signaling in CLL cells (37), further indicating that XIAP may be a relevant target in CLL.…”

Section: Discussionmentioning

confidence: 94%

“…Among the IAP family members, it is especially X-linked IAP (XIAP) that is known for its antiapoptotic function (20). Interestingly, high levels of XIAP were detected in CLL cells, possibly as part of a NF-κB-regulated survival program (20)(21)(22). Because XIAP blocks apoptosis at a central point via inhibition of caspases, there is currently much interest to exploit XIAP as a molecular target in human cancers (19).…”

Section: Introductionmentioning

confidence: 99%

A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

et al. 2009

View full text Add to dashboard Cite

Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V H genes). Interestingly, cases with unmutated V H genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V H gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL. [Cancer Res 2009;69(23):8977-86]

show abstract

“…Possibly, these high levels of Smac in CLL could prevent the inhibitory effect of XIAP on caspases, since in conditions where XIAP is upregulated and apoptosis is prevented, there's no caspase inhibition (Schliep et al, 2004;Winkler et al, 2005). However, downregulation of Smac has been also observed in CLL samples.…”

Section: Chronic Lymphocytic Leukemia (Cll)mentioning

confidence: 96%