| 11. |
- Kanduri, Meena, et al.
(författare)
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The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia
- 2011
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 1, s. e12-
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear factor-kappa B (NF-kappa B) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-kappa B inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of I kappa B alpha by IkB kinases, thus preventing NF-kappa B release. In this study, we investigated if IMD-0354 can inhibit NF-kappa B activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-kappa B were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-kappa B in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.
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| 12. |
- Marincevic, Millaray, 1983-, et al.
(författare)
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Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B cell receptors
- 2010
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 95:12, s. 2072-2079
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Tidskriftsartikel (refereegranskat)abstract
- Background Numerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with "stereotyped" B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level. DESIGN AND METHODS: We investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays. RESULTS: Although generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients. Conclusions Our novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.
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| 13. |
- Martinelli, Silvia, et al.
(författare)
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ANGPT2 promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia
- 2013
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:7, s. 720-729
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence suggests a key role for angiopoietin-2 (ANGPT2) in influencing the aggressiveness of chronic lymphocytic leukemia (CLL). In the presence of vascular endothelial growth factor (VEGF), ANGPT2 causes vessel destabilization leading to neoangiogenesis. Accordingly, high expression levels of ANGPT2 and high degree of angiogenesis have consistently been associated with poor prognosis in CLL; however, the molecular mechanisms behind the variability in ANGPT2 expression are still to be discovered. Here, for the first time, we investigated the DNA methylation status of the ANGPT2 promoter in a large CLL cohort (n = 88) using pyrosequencing and correlated methylation data with ANGPT2 expression levels, prognostic factors and outcome. Importantly, methylation levels of the ANGPT2 gene correlated inversely with its mRNA expression levels (p < 0.001). Moreover, low ANGPT2 methylation status was highly associated with adverse prognostic markers, shorter time to first treatment and overall survival. Finally, treatment with methyl inhibitors induced re-expression of ANGPT2 in two B-cell lymphoma cell lines, underscoring the importance of DNA methylation in regulating transcriptional silencing of this gene. In conclusion, we believe that the known variability in ANGPT2 expression among CLL patients could be explained by differential promoter DNA methylation and that low methylation levels of the ANGPT2 promoter have an adverse prognostic impact in CLL.
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| 14. |
- Norberg, Maria, et al.
(författare)
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Screening for Cytotoxic Compounds in Poor-prognostic Chronic Lymphocytic Leukemia
- 2012
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 32:8, s. 3125-3136
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: For chronic lymphocytic leukemia (CLL) patients with poor-prognostic genomic aberrations the therapeutic options are limited. We used the Spectrum Collection library to identify compounds with anti-leukemia activity in high-risk CLL.Materials and Methods: We identified substances with equal high cytotoxic activity in vitro in samples from poor-prognostic CLL (11q-/17p-, n=3) as compared to those from favourable-prognostic CLL (13q-, n=3). Cell survival was measured by fluorometric microculture cytotoxicity assay.Results: Out of 2,000 compounds, 65 had a similar effect in both prognostic groups. Fifteen compounds were selected for dose-response experiments in 16 additional CLL samples. Of these compounds, 12 continued to have similar cytotoxicity between prognostic subgroups. Additional experiments demonstrated that in CLL cells with 11q or 17p deletion, 5-azacytidine induced apoptosis in a dose-dependent manner and lipoprotein lipase expression was reduced following orlistat treatment.Conclusion: Using primary cultures of cells from high-risk CLL patients for compound screening is a feasible approach and that 5-azacytidine and orlistat exemplify substances that exhibit cytotoxicity in poor-risk CLL.
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| 15. |
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| 16. |
- Staffas, Anna, 1982, et al.
(författare)
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Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:22, s. 5905-5913
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Tidskriftsartikel (refereegranskat)abstract
- Mutation status of the FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in pediatric AML patients enrolled in the NOPHO 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients respectively. Presence of FLT3-ITD was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of pediatric AML patients and that determination of the BAALC gene expression level can add valuable information.
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| 17. |
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| 18. |
- Zainuddin, Norafiza, 1978-, et al.
(författare)
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Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma
- 2011
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 35:4, s. 438-443
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Tidskriftsartikel (refereegranskat)abstract
- The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients’ clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048), the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.
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| 19. |
- Zainuddin, Norafiza, 1978-, et al.
(författare)
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TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia
- 2011
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 35:2, s. 272-274
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations in the absence of 17p-deletion correlate with rapid disease progression and poor survival in chronic lymphocytic leukemia (CLL). Herein, we determined the TP53 mutation frequency in 268 newly diagnosed CLL patients from a population-based material. Overall, we detected TP53 mutations in 3.7% of patients (n= 10), where 7/10 cases showed a concomitant 17p-deletion, confirming the high prevalence of TP53 mutation in 17p-deleted patients. Only 3 (1.1%) of the newly diagnosed patients in our cohort thereby carried TP53 mutations without 17p-deletion, a frequency that is much lower than previous reports on referral cohorts (3-6%). Our findings imply that TP53 mutations are rare at CLL onset and instead may arise during disease progression.
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