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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 by quantitative RT-PCR using the independent Set-C patients. (A) Expression in log2, of mean relative levels of TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9 in TEL/AML1-positive (n = 7) and TEL/AML1-negative (n = 20) Set-C samples.LSP1 and CD9 are significantly (P < 0.01) under-expressed in TEL/AML1-positive ALL patients and each of the seven other genes is significantly (with either P < 0.01* or P < 0.05**) over-expressed in TEL/AML1-positive ALL patients; these findings agree with microarray data obtained with Set-A and Set-B patients. (B) Hierarchical clustering analysis (Euclidean distance and complete linkage) of Set-C patients using quantitative RT-PCR data for the nine tested genes. The dendrogram clearly distinguishes TEL/AML1-positive patients from TEL/AML1-negative patients.
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Figure 5: Validation of the selected genes for TEL/AML1 by quantitative RT-PCR using the independent Set-C patients. (A) Expression in log2, of mean relative levels of TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9 in TEL/AML1-positive (n = 7) and TEL/AML1-negative (n = 20) Set-C samples.LSP1 and CD9 are significantly (P < 0.01) under-expressed in TEL/AML1-positive ALL patients and each of the seven other genes is significantly (with either P < 0.01* or P < 0.05**) over-expressed in TEL/AML1-positive ALL patients; these findings agree with microarray data obtained with Set-A and Set-B patients. (B) Hierarchical clustering analysis (Euclidean distance and complete linkage) of Set-C patients using quantitative RT-PCR data for the nine tested genes. The dendrogram clearly distinguishes TEL/AML1-positive patients from TEL/AML1-negative patients.

Mentions: Second, gene expressions were quantified using real-time RT-PCR with the independent Set-C patients. Nine genes (TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9) were chosen from the 14 selected above as being the most relevant biologically and able on their own to segregate Set-A and -B patients into appropriate clusters (TEL/AML1-positive versus TEL/AML1-negative; data not shown). Despite the genetic variability observed within each group (highlighted by the SD values), the mean gene expression values were significant according to Student's t-test, with either a P < 0.05 or < 0.01. TCFL5, PIK3C3, CBFA2T3, RUNX1, EGFL7, TP53INP1 and TNFRSF7 were over-expressed and CD9 and LSP1 under-expressed in the TEL/AML1-positive ALL relative to the TEL/AML1-negative subgroup, consistent with the microarray findings (Figure 5A). Hierarchical clustering of Set-C patient data using these nine genes segregated TEL/AML1-positive patients into one distinct branch (Figure 5B).


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 by quantitative RT-PCR using the independent Set-C patients. (A) Expression in log2, of mean relative levels of TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9 in TEL/AML1-positive (n = 7) and TEL/AML1-negative (n = 20) Set-C samples.LSP1 and CD9 are significantly (P < 0.01) under-expressed in TEL/AML1-positive ALL patients and each of the seven other genes is significantly (with either P < 0.01* or P < 0.05**) over-expressed in TEL/AML1-positive ALL patients; these findings agree with microarray data obtained with Set-A and Set-B patients. (B) Hierarchical clustering analysis (Euclidean distance and complete linkage) of Set-C patients using quantitative RT-PCR data for the nine tested genes. The dendrogram clearly distinguishes TEL/AML1-positive patients from TEL/AML1-negative patients.
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Related In: Results  -  Collection

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Figure 5: Validation of the selected genes for TEL/AML1 by quantitative RT-PCR using the independent Set-C patients. (A) Expression in log2, of mean relative levels of TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9 in TEL/AML1-positive (n = 7) and TEL/AML1-negative (n = 20) Set-C samples.LSP1 and CD9 are significantly (P < 0.01) under-expressed in TEL/AML1-positive ALL patients and each of the seven other genes is significantly (with either P < 0.01* or P < 0.05**) over-expressed in TEL/AML1-positive ALL patients; these findings agree with microarray data obtained with Set-A and Set-B patients. (B) Hierarchical clustering analysis (Euclidean distance and complete linkage) of Set-C patients using quantitative RT-PCR data for the nine tested genes. The dendrogram clearly distinguishes TEL/AML1-positive patients from TEL/AML1-negative patients.
Mentions: Second, gene expressions were quantified using real-time RT-PCR with the independent Set-C patients. Nine genes (TCFL5, PIK3C3, CBFA2T3, TNFRSF7, RUNX1, EGFL7, TP53INP1, LSP1 and CD9) were chosen from the 14 selected above as being the most relevant biologically and able on their own to segregate Set-A and -B patients into appropriate clusters (TEL/AML1-positive versus TEL/AML1-negative; data not shown). Despite the genetic variability observed within each group (highlighted by the SD values), the mean gene expression values were significant according to Student's t-test, with either a P < 0.05 or < 0.01. TCFL5, PIK3C3, CBFA2T3, RUNX1, EGFL7, TP53INP1 and TNFRSF7 were over-expressed and CD9 and LSP1 under-expressed in the TEL/AML1-positive ALL relative to the TEL/AML1-negative subgroup, consistent with the microarray findings (Figure 5A). Hierarchical clustering of Set-C patient data using these nine genes segregated TEL/AML1-positive patients into one distinct branch (Figure 5B).

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