Biological and Clinical Relevance of Surrogate Markers of IgVH Mutational Status in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1062-1062
Author(s):  
Fortunato Morabito ◽  
Marta Lionetti ◽  
Giovanna Cutrona ◽  
Katia Todoerti ◽  
Serena Matis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Candidate Genes ◽  
Lymphocytic Leukemia ◽  
Surrogate Markers ◽  
Rt Pcr ◽  
Mutation Status ◽  
Expression Levels ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease; some patients have a rapidly progressing disease and others exhibit an indolent course and survive for many years without treatment. Mutation status of IgVH genes utilized by CLL cells represents a very reliable predictor of clinical outcome in B-CLL, but its analysis is expensive and beyond the capacities of most diagnostic laboratories. To identify surrogate markers we performed a gene expression profiling analysis of CD19+ purified cells from 80 B-CLL untreated patients in Binet stage A, by means of Affymetrix GeneChip® HGU133A arrays. The comparison of 46 IgVH-unmutated versus 34 mutated samples using the Prediction Analysis of Microarrays software identified 78 differentially expressed probes, specific for 59 well-characterized genes. Specifically, 43 genes had a higher and 16 genes a lower average expression in the IgVH unmutated group. These genes are involved in cellular functions, including cell cycle regulation (SEPT7, SEPT10, CDK2AP1), cell proliferation (SLAMF1, LDOC1), apoptosis (CD63, IFT57, P2RX1, RNF130, TNFRSF1B), cell adhesion (CNTNAP2, C1orf38, PCDH9), immune response (ZAP70, IFI44), signal transduction (AKAP13, RASGRP1, USP6NL, TGFBR3, AKAP12), lipid metabolism and fatty-acid degradation (FADS3, LPL, LASS6), cell-cell signalling (FCRL2), phospholipid biosynthetic process (AYTL2), regulation of circadian rhythm (EGR3, CRY1, OPN3), DNA-dependent regulation of transcription (MYBL1, NR4A2, NRIP1, ZBTB20), muscle development (VAMP5, SRI, DMD). The expression signature identified in the proprietary database was then validated by means of a meta-analysis of a publicly available gene expression dataset of 100 B-CLL (Haslinger et al., 2005), showing classification accuracy measures leading to a global classification rate of 82.93% of the test set and thus suggesting the strength of the identified expression signature. The expression levels of 11 genes (LPL, ZBTB20, ZAP70, CRY1, COBLL1, SEPT10, LDOC1, TNFRSF1B, DMD, SRI, NRIP1) were confirmed by means of quantitative real-time PCR (Q-RT-PCR) in a subset of 40 CLL patients. The prognostic impact for Time To Treatment (TTT) of the 59 candidate genes of our classifier model was investigated in 77 patients. Forty-nine (36.4%) of these received treatment after a median follow up of 4 years. As expected, patients with unmutated IgVH genes had a risk of therapy requirement that was about 3 times higher (HR: 3.1,95% C.I. 1.6–5.8, p<0.0001) than those with mutated IgVH. Based on microarray expression levels, 43/59 genes significantly predicted TTT with a HR ranging from 1.5 (LPL gene) to 4.2 (SRI gene) (value for ZAP-70 = HR: 1.9, 95% C.I. 1.0–3.4, p=0.039). The same analysis performed in the panel of the 11 genes validated by Q-RT-PCR revealed 4 candidate genes which significantly predicted TTT. Specifically, Cox univariate analysis confirmed ZAP-70 as a predictor of disease outcome and underscored the prognostic role of the LPL, TNFRSF1B and CRY1 genes. The predictive power of the novel putative surrogate markers for the IgVH mutation status is now being further validated at protein expression level.

scholarly journals Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

2001 ◽  
Vol 194 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Andreas Rosenwald ◽  
Ash A. Alizadeh ◽  
George Widhopf ◽  
Richard Simon ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Gene Expression Signature ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Human Leukemia ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status

2004 ◽  
Vol 22 (19) ◽  
pp. 3937-3949 ◽  
Author(s):  
Christian Haslinger ◽  
Norbert Schweifer ◽  
Stephan Stilgenbauer ◽  
Hartmut Döhner ◽  
Peter Lichter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Differentially Expressed Genes ◽  
Expression Profiling ◽  
Lymphocytic Leukemia ◽  
Differentially Expressed ◽  
Mutational Status ◽  
Genomic Aberrations ◽  
Cell Chronic Lymphocytic Leukemia

Purpose Genomic aberrations and mutational status of the immunoglobulin variable heavy chain (VH) gene have been shown to be among the most important predictors for outcome in patients with B-cell chronic lymphocytic leukemia (B-CLL). In this study, we report on differential gene expression patterns that are characteristic for genetically defined B-CLL subtypes. Materials and Methods One hundred genetically well-characterized B-CLL samples, together with 11 healthy control samples, were analyzed using oligonucleotide arrays, which test for the expression of some 12,000 human genes. Results Aiming at microarray-based subclassification, class predictors were constructed using sets of differentially expressed genes, which yielded in zero or low misclassification rates. Furthermore, a significant number of the differentially expressed genes clustered in chromosomal regions affected by the respective genomic losses/gains. Deletions affecting chromosome bands 11q22-q23 and 17p13 led to a reduced expression of the corresponding genes, such as ATM and p53, while trisomy 12 resulted in the upregulation of genes mapping to chromosome arm 12q. Using an unsupervised analysis algorithm, expression profiling allowed partitioning into predominantly VH-mutated versus unmutated patient groups; however, association of the expression profile with the VH mutational status could only be detected in male patients. Conclusion The finding that the most significantly differentially expressed genes are located in the corresponding aberrant chromosomal regions indicates that a gene dosage effect may exert a pathogenic role in B-CLL. The significant difference in the partitioning of male and female B-CLL samples suggests that the genomic signature for the VH mutational status might be sex-related.

scholarly journals Study of fibromodulin gene expression in B-cell chronic lymphocytic leukemia

2011 ◽  
Vol 23 (1) ◽  
pp. 11-15 ◽  
Author(s):  
Doha Abd El-hamid Hassan ◽  
Rania Mohamed Samy ◽  
Osama Taha Abd-Elrahim ◽  
Caroline Sabry Salib
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Strong correlation between VEGF and MCL-1 mRNA expression levels in B-cell chronic lymphocytic leukemia

2009 ◽  
Vol 33 (12) ◽  
pp. 1623-1626 ◽  
Author(s):  
Lauren Véronèse ◽  
Olivier Tournilhac ◽  
Pierre Verrelle ◽  
Frédéric Davi ◽  
Guillaume Dighiero ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Expression ◽  
Strong Correlation ◽  
Lymphocytic Leukemia ◽  
Expression Levels ◽  
Mrna Expression Levels ◽  
Cell Chronic Lymphocytic Leukemia

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 681-689 ◽  
Author(s):  
Susann Fält ◽  
Mats Merup ◽  
Gerard Tobin ◽  
Ulf Thunberg ◽  
Gösta Gahrton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Cycle Control ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Protein Kinase Activity ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The usage of the immunoglobulin (Ig) VH3-21 gene is associated with poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) despite VH gene mutation status. Many VH3-21+ patients also display restricted heavy- and light-chain Ig gene rearrangements, implying a role of antigen selection in disease development. To explore the specific phenotypic/genotypic features among VH3-21+ B-CLLs, we compared gene expression patterns in 15 VH3-21+ and 24 non-VH3-21 patients (11 with unmutated and 13 with mutated VH genes) using Affymetrix microarray analysis (∼12 500 genes). A distinct expression profile was identified for VH3-21+ patients in contrast to the Ig-unmutated and -mutated groups. By applying different algorithms, the data enabled an efficient class discrimination of the VH3-21+ subset based on 27 or 57 genes. A set of genes was sorted out which, using different analytical methods, consistently gave a distinction between VH3-21+ and non-VH3-21 samples. Several of these genes are involved in regulation of DNA replication/cell-cycle control, transcription and protein kinase activity, which may render the VH3-21+ cells with a higher proliferative drive. However, no clear evidence of increased B-cell receptor signaling was found in the VH3-21+ group. Altogether, our identification of a specific VH3-21 profile may provide insights into the pathogenesis of the VH3-21+ subgroup. (Blood. 2005;106:681-689)

B-Cell Chronic Lymphocytic Leukemia Cells Exposed to the Non-Genotoxic p53 Activator Nutlin-3 Are Characterized by a Specific Gene Expression Signature.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4374-4374
Author(s):  
Michele Dal-Bo ◽  
Paola Secchiero ◽  
Massimo Degan ◽  
Riccardo Bomben ◽  
Dania Benedetti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Differentially Expressed Genes ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Differentially Expressed ◽  
Specific Gene ◽  
P53 Mutations ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4374 Introduction p53 plays a key role in determining the clinical features of B cell chronic lymphocytic leukemia (CLL). Disruption of p53 by point mutations, deletion at 17p13, or both, occurs in a fraction of cases at diagnosis and predicts poor survival and chemorefractoriness. In cells with functional p53, p53 activity is inhibited through interaction with MDM2. In fact, p53 can be activated upon exposure of cells to inhibitors of p53/MDM2 interaction, like Nutlins. Exposure of CLL cells to Nutlin-3 is effective in raising the levels of p53 protein with subsequent induction of cell cycle arrest and/or apoptosis, independently of the most relevant prognostic markers. The aim of the present study was to analyze the gene expression profile (GEP) induced by Nutlin-3 exposure in primary CLL cells from p53wt and p53del/mut cases. Patients and methods purified cells from 24 PB CLL samples, all characterized for IGHV mutational status, CD38 and ZAP-70 and p53 mutations (16 p53wt CLL, 8 p53del/mut CLL of which 6 with del17p13 and p53 mutations, 1 with del17p13 alone, and 1 with p53 mutations alone), were exposed to 10 mM Nutlin-3 for 24 hours. GEP was performed using a dual labelling strategy; the differential expression of the below reported genes were validated by quantitative real-time PCR. Results i) signature of Nutlin-3 exposure in p53wt CLL: 144 differentially expressed genes (143 up-regulated, 1 down-regulated) were correlated with response to Nutlin-3. Among the over-expressed genes, several genes were related to apoptosis (e.g. BAX, BBC3, E124, IKIP, FAS, LRDD, FLJ11259, TRIAP1, GADD45, TP53INP1, ISG20L1, ZMAT3, TNFRS10C, TNFRSF10B/TRAIL-R2), while other genes (e.g. MDM2, CDKN1A, PCNA) were up-regulated by Nutlin-3 as a part of a negative feed-back mechanism. Of note, this signature was not shared by 3/16 p53wt cases (identified as “non-responder” p53wt CLL) and 7/8 p53del/mut cases (identified as “non-responder” p53del/mut CLL); consistently, cells from these cases were also significantly resistant to the in-vitro cytotoxic effects of Nutlin-3; ii) signature of Nutlin-3 “non-responder” p53wt CLL: by comparing the constitutive GEP of 13 “responder” versus 3 “non-responder” p53wt CLL, we obtained 278 differentially expressed genes, 149 up-regulated and 129 down-regulated in “non-responder” p53wt CLL. Among up-regulated genes, we focused on MDM4/MDMX, a gene whose product was known to have an inhibitor activity of p53-dependent transcription and to form Nutlin-3 resistant complexes with p53. Among down-regulated genes, validations were made for BIRC4BP, whose product is known to act as an antagonist of the anti-apoptotic protein XIAP; iii) signature of Nutlin-3 “non-responder” p53del/mut CLL: by comparing the constitutive GEP of 13 “responder” versus 7 “non-responder” p53del/mut cases, we obtained 72 differentially expressed genes, 26 up-regulated and 46 down-regulated (31/46 located at the 17p segment) in “non-responder” p53del/mut CLL. Validations were made for several genes whose products display pro-apoptotic activities (e.g. PSMB6, RPL26 and ZBTB4, located at 17p segment, and GNAZ located at chromosome 22) among down-regulated genes, and ARHGDIA, whose gene product displays anti-apoptotic activities and mediates cellular resistance to chemotherapeutic agents, among up-regulated genes. Notably, CLL cells (n=43) displayed constitutively higher levels of MDM4/MDMX (p<0.0001) and ARHGDIA (p=0.0002) transcripts than purified normal B cells (n=15), irrespectively to the major biologic prognosticators. Conclusions specific gene-sets and GEP were documented to be associated with response or resistance to Nutlin-3 exposure in p53wt or p53del/mut CLL. These findings may help to identify novel molecular targets for CLL therapy. Disclosures: No relevant conflicts of interest to declare.

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