Profiling of apoptosis genes allows for clinical stratification of primary nodal diffuse large B‐cell lymphomas

Muris, Jettie J.F.; Ylstra, Bauke; Cillessen, Saskia A.G.M.; Ossenkoppele, Gert J.; Kluin-Nelemans, Hanneke C.; Eijk, Paul P.; Nota, Benjamin; Tijssen, Marianne; Boer, Wim P.H. de; Wiel, Mark A. van de; IJssel, Paul R.L.A. van den; Jansen, Patty M.; Bruin, Peter C. de; Krieken, J. Han J.M. van; Meijer, Gerrit A.; Meijer, Chris J.L.M.; Oudejans, Joost J.

doi:10.1111/j.1365-2141.2006.06375.x

Cited by 40 publications

(54 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our previous expression microarray results (18) and with a previous study by Davis et al (28), we have found that cases with high levels of proapoptotic and antiapoptotic genes are frequently clinically refractory to chemotherapy. Although the association between high expression levels of antiapoptotic genes and a poor response to chemotherapy has been shown by many other studies (2 -4, 10 -12), the high expression levels of proapoptotic genes in chemotherapy-resistant cases were unexpected.…”

Section: Discussionsupporting

confidence: 93%

“…Using microarray expression analysis, we have recently shown that a subset of chemotherapy-refractory DLBCL is characterized by high expression levels of proapoptotic genes, particularly genes that are under transcriptional control of p53 and are involved in the intrinsic, caspase-9 -mediated apoptosis pathway (18). These DLBCL samples were also characterized by high expression levels of apoptosis-inhibiting genes, providing an explanation of why expression of proapoptotic genes does not result in effective induction of apoptosis.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma

Cillessen

Hess

Hooijberg

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Inhibition of the apoptosis cascade is an important cause of therapy resistance in diffuse large B-cell lymphomas (DLBCL). In this study, we investigated possible mechanisms and expression levels of apoptosis-related genes in the apoptosis pathway that may be responsible for differences in chemotherapy sensitivity between DLBCL patients. Experimental Design: Twenty-eight DLBCL patient samples were investigated for their expression levels of apoptosis-related genes using reverse transcription-multiplex ligation-dependent probe amplification analysis. Functional analysis of the intrinsic, caspase-9^mediated pathway was done using fluorescence-activated cell sorting analysis,Western blot analysis, and immunohistochemistry. Results:Two DLBCL groups were identified: one with low expression levels of both proapoptotic and antiapoptotic genes and one group with high expression levels of these genes. DLBCL with high expression levels of proapoptotic and antiapoptotic genes frequently seemed to be refractory to clinical chemotherapy. Functional analysis in these latter DLBCL samples and DLBCL cell lines with comparable expression profiles revealed high levels of spontaneous caspase-9 activity without induction of apoptosis, indicating disruption of the apoptosis pathway downstream of caspase-9 activation. This disruption of the apoptosis pathway could be restored using a smallmolecule XIAP antagonist. Conclusions: We conclude that the intrinsic, caspase-9^mediated apoptosis pathway is constitutively activated in part of chemotherapy-refractory DLBCL with concomitant downstream inhibition of the convergence apoptosis pathway and that inhibition of XIAP might be an alternative therapy for chemotherapy-refractory DLBCL.

show abstract

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma

Cillessen

Hess

Hooijberg

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…This suggestion is supported by the observation that resistance to chemotherapy in DLBCL may be linked to upregulation of anti-apoptotic NF-κB regulated genes, including Bcl-2 and XIAP. The potential importance of investigating such approaches to DLBCL sub-classification has been highlighted in recent publications, which have addressed this subject (32,33). Specific IAP proteins (cIAP1, cIAP2 and XIAP) have been shown to be differentially regulated in a variety of lymphomas, including DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotyping of diffuse large B-cell lymphoma (DLBCL) defines multiple sub-groups of germinal centre-like tumours displaying different survival characteristics

Anderson

Fordham²,

Overman³

et al. 2009

Int J Oncol

View full text Add to dashboard Cite

Abstract. Diffuse large B-cell lymphoma (DLBCL) forms a heterogeneous collection of aggressive non-Hodgkin's Lymphoma in which three principle classes of neoplasia have been defined according to gene expression and immunophenotyping studies. The present investigation sought to examine the immunophenotype of proposed subgroups and relate these to patient survival. A series of 155 DLBCL treated uniformly with anthracycline therapy in clinical trials, were stratified upon the basis of common biomarker expression with combination immunophenotype being related to patient overall survival. Stratification of tumours with respect to combined expression profiles of the three biological markers (CD10, Bcl-6 and MUM-1) revealed six groups showing significant differences in survival (p=0.014). The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6 + , MUM-1 -and the second CD10 + Bcl-6 + MUM-1 + (p=0.002). The former group displayed median survival time of 143 months, the latter only 11 months. A third population of GC tumours (CD10 + Bcl-6 + and MUM-1 -) also displayed a relative short median survival (32 months). Of the three groups presenting a non-GC or activated B cell (NGC/ ABC) phenotype, only one (CD10 -, Bcl-6 + and MUM-1 + ) presented short-term median survival (27 months) comparable with poor prognosis GC sub-populations. Within the remaining ABC tumour groups (CD10 -Bcl-6 -MUM-1 -and CD10 -Bcl-6 -MUM-1 + ) patients presented intermediate median survival times of 54 and 58 months, respectively. Thus, the GC phenotype did not act as a universal indicator of good clinical prognosis, but rather multiple groups of GC tumours were associated with distinct overall survival profiles. Ultimately, the data allowed definition of a predictive algorithm defining three groups predicting poor, intermediate and good clinical prognosis. The first of these comprised two patient subpopulations with GC-like tumours together with one subpopulation of NGC/ABC, the second two sub-populations of ABC-like tumours, and the final a single group of GC-like tumours associated with optimal long-term survival.

show abstract

“…cDNA synthesis, hybridization and scanning were performed as described previously. [27][28][29] To investigate reproducibility of the hybridizations, technical replicates were included of RNA isolated from primary keratinocytes (EK2000-12), SiHa cells and the FK16A#6 hybrid MCF15cl8. The resulting expression profiles of each of the replicates were highly comparable.…”

Section: Rna Isolationmentioning

confidence: 99%

“…These findings underline the reliability of the data obtained, as was also found in previous studies in which validation of the same micro array platform has been described. [28][29][30] …”

Section: Rna Isolationmentioning

confidence: 99%

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Wilde

Wilting

Meijer

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16-immortalized keratinocyte cell line FK16A and in the HPV16-containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV-transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, 4 of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. Moreover, increased MGP protein expression was significantly more frequent in high-grade cervical premalignant lesions with elevated hTERT mRNA expression compared to those without. In summary, we identified 32 candidate biomarkers for deregulated hTERT mRNA expression, which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. ' 2007 Wiley-Liss, Inc.Key words: HPV; hTERT; telomerase; cervical carcinogenesis; microarray expression analysis The main risk factor for the development of cervical cancer is infection with high-risk human papillomavirus (hrHPV), 1 which is supported by the detection of hrHPV in virtually all cervical carcinomas. 2 Cervical cancer evolves from preexisting noninvasive premalignant lesions referred to as cervical intraepithelial neoplasia (CIN), graded CIN1 to CIN3. Progression of an hrHPV infected CIN lesion to invasive cancer is a result of further specific (epi)genetic alterations within the host cell genome. 3,4 One of the consequences that is crucial for tumor development is an increased activity of telomerase. 5,6 Telomerase is a ribonucleoprotein that can elongate the chromosomal ends or telomeres, thereby compensating for telomere shortening that is inherent to DNA replication. 7 Whereas most cancer cells display elevated telomerase activity and stabilized telomeres, resulting in an unlimited lifespan, most primary somatic cells exhibit absence of detectable telomerase activity and continuous telomere erosion during cell division. The latter ultimately leads to the induction of senescence. 7 Telomerase consists of several subunits, including a structural RNA component (hTR) that serves as a template dur...

show abstract

Profiling of apoptosis genes allows for clinical stratification of primary nodal diffuse large B‐cell lymphomas

Cited by 40 publications

References 41 publications

Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma

Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma

Immunophenotyping of diffuse large B-cell lymphoma (DLBCL) defines multiple sub-groups of germinal centre-like tumours displaying different survival characteristics

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

Contact Info

Product

Resources

About