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Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia.

Gandemer V, Rio AG, de Tayrac M, Sibut V, Mottier S, Ly Sunnaram B, Henry C, Monnier A, Berthou C, Le Gall E, Le Treut A, Schmitt C, Le Gall JY, Mosser J, Galibert MD - BMC Genomics (2007)

Bottom Line: We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation.These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples).Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

View Article: PubMed Central - HTML - PubMed

Affiliation: CNRS UMR 6061 Laboratoire de Génétique et Développement, Equipe Régulation transcriptionnelle et oncogenèse, Université de Rennes-1, Faculté de Médecine, IFR140 GFAS, 2 av du Pr Léon Bernard, CS 34317, Rennes cedex, France. virginie.gandemer@chu-rennes.fr

ABSTRACT

Background: The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR.

Results: We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI - highlighting the biology of the TEL/AML1 sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of RUNX1 (AML1) was further investigated and in one third of the patients correlated with cytogenetic findings.

Conclusion: Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

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Validation of the selected genes for TEL/AML1 using Set-B microarray data. (A) Hierarchical clustering analyses (Euclidean distance and average linkage) of Set-B microarray data using the 14 selected genes for TEL/AML1. Patients are segregated according to the presence or absence of the TEL/AML1 rearrangement. (B) Support tree of Set-A and Set-B patients using the 14 selected genes for TEL/AML1. Two branches clearly distinguished TEL/AML1-positive ALL and TEL/AML1-negative ALL with 100% of reproducibility when resampling with replacement was conducted on experiments and genes for 100 iterations. The expression levels of the RUNX1 gene can explain the clustering of patients 9 and 17.
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Figure 4: Validation of the selected genes for TEL/AML1 using Set-B microarray data. (A) Hierarchical clustering analyses (Euclidean distance and average linkage) of Set-B microarray data using the 14 selected genes for TEL/AML1. Patients are segregated according to the presence or absence of the TEL/AML1 rearrangement. (B) Support tree of Set-A and Set-B patients using the 14 selected genes for TEL/AML1. Two branches clearly distinguished TEL/AML1-positive ALL and TEL/AML1-negative ALL with 100% of reproducibility when resampling with replacement was conducted on experiments and genes for 100 iterations. The expression levels of the RUNX1 gene can explain the clustering of patients 9 and 17.

Mentions: We validated the microarray results in two steps. First, we used a new microarray data set (Set-B) to perform clustering analysis based on the 14 selected genes (RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI). Confirming the Set-A results, the TEL/AML1-positive ALL patients were grouped together in one branch (Figure 4A) separate from TEL/AML1-negative ALL patients, whose blast cells did not contain any recurrent chromosomal translocation. Additionally, hierarchical clustering and bootstrapping of data for Set-A and Set-B patients, using these 14 genes, satisfactorily segregated the TEL/AML1-positive patients into one branch (Figure 4B). As in the analysis described above, patient 9 (TEL/AML1-negative) and patient 17 (TEL/AML1-positive) did not classify according to their chromosomal rearrangement.


Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia.

Gandemer V, Rio AG, de Tayrac M, Sibut V, Mottier S, Ly Sunnaram B, Henry C, Monnier A, Berthou C, Le Gall E, Le Treut A, Schmitt C, Le Gall JY, Mosser J, Galibert MD - BMC Genomics (2007)

Validation of the selected genes for TEL/AML1 using Set-B microarray data. (A) Hierarchical clustering analyses (Euclidean distance and average linkage) of Set-B microarray data using the 14 selected genes for TEL/AML1. Patients are segregated according to the presence or absence of the TEL/AML1 rearrangement. (B) Support tree of Set-A and Set-B patients using the 14 selected genes for TEL/AML1. Two branches clearly distinguished TEL/AML1-positive ALL and TEL/AML1-negative ALL with 100% of reproducibility when resampling with replacement was conducted on experiments and genes for 100 iterations. The expression levels of the RUNX1 gene can explain the clustering of patients 9 and 17.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2211320&req=5

Figure 4: Validation of the selected genes for TEL/AML1 using Set-B microarray data. (A) Hierarchical clustering analyses (Euclidean distance and average linkage) of Set-B microarray data using the 14 selected genes for TEL/AML1. Patients are segregated according to the presence or absence of the TEL/AML1 rearrangement. (B) Support tree of Set-A and Set-B patients using the 14 selected genes for TEL/AML1. Two branches clearly distinguished TEL/AML1-positive ALL and TEL/AML1-negative ALL with 100% of reproducibility when resampling with replacement was conducted on experiments and genes for 100 iterations. The expression levels of the RUNX1 gene can explain the clustering of patients 9 and 17.
Mentions: We validated the microarray results in two steps. First, we used a new microarray data set (Set-B) to perform clustering analysis based on the 14 selected genes (RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI). Confirming the Set-A results, the TEL/AML1-positive ALL patients were grouped together in one branch (Figure 4A) separate from TEL/AML1-negative ALL patients, whose blast cells did not contain any recurrent chromosomal translocation. Additionally, hierarchical clustering and bootstrapping of data for Set-A and Set-B patients, using these 14 genes, satisfactorily segregated the TEL/AML1-positive patients into one branch (Figure 4B). As in the analysis described above, patient 9 (TEL/AML1-negative) and patient 17 (TEL/AML1-positive) did not classify according to their chromosomal rearrangement.

Bottom Line: We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation.These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples).Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

View Article: PubMed Central - HTML - PubMed

Affiliation: CNRS UMR 6061 Laboratoire de Génétique et Développement, Equipe Régulation transcriptionnelle et oncogenèse, Université de Rennes-1, Faculté de Médecine, IFR140 GFAS, 2 av du Pr Léon Bernard, CS 34317, Rennes cedex, France. virginie.gandemer@chu-rennes.fr

ABSTRACT

Background: The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR.

Results: We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI - highlighting the biology of the TEL/AML1 sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of RUNX1 (AML1) was further investigated and in one third of the patients correlated with cytogenetic findings.

Conclusion: Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

Show MeSH
Related in: MedlinePlus