INFANT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA SHOWS CHARACTERISTIC GENETIC FEATURES COMPARED TO CHILDHOOD CASES
(Abstract release date: 05/19/16)
EHA Library. Hoell J. 06/09/16; 132393; E844
Disclosure(s): This work was funded by the parents’ initiative of the department of pediatric oncology (Elterninitiative Kinderkrebsklinik) Düsseldorf, the Duesseldorf School of Oncology (funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Duesseldorf) and the Deutsche Forschungsgemeinschaft (DFG, HO 5456/3-1).
Dr. Jessica Hoell
Contributions
Contributions
Abstract
Abstract: E844
Type: Eposter Presentation
Background
Survival rates of infants (< 1 year of age) diagnosed with acute lymphoblastic leukemia (ALL) remain poor with a 4-year event free survival of 47% (Interfant-99). Beside their often highly aggressive initial clinical presentation, these patients usually do not respond well to current therapies. For reasons not yet understood, nearly all of those patients present with B cell-ALL with T cell-ALL remaining an absolute rarity in infants.
Aims
Given its rarity, the biology of infant T-ALL is not understood. Also, it is not clear whether it presents a distinct disease compared to T-ALL diagnosed in later childhood. The aim of our present study therefore was to identify the landscape of genetic alterations of infant T-ALL by whole-exome sequencing (WES), transcriptome and microRNA sequencing.
Methods
We analyzed a total of three infant T-ALL patients and six childhood T-ALL patients as comparison. All sequencing was performed on a HiSeq 2500 (Illumina). Obtained sequence reads were aligned to the human reference genome. Resulting variation calls were annotated by Variant Effect Predictor. MuTect and VarScan2 were employed for identification of somatic nucleotide variations (SNVs). Correlation analyses based on public databases for miRNA-mRNA targeting were performed to reveal miRNA-mRNA pairs expressed in a negative correlation fashion.
Results
In total, 4504 genes had SNVs in any of the three infant patients, 1305 were recurrent in at least two and 557 in all three infant patients. We did not detect any SNVs in Notch1, however, we found SNVs in Notch2 and Notch3. On transcriptome level, 676 genes were differentially expressed (│logFC│ ≥ 1, FDR < 0.05) between the patient groups. Out of these genes, 194 were downregulated in infants and 482 were upregulated when compared to childhood cases. The hierarchical clustering of these significantly differentially expressed genes clearly separated the two patient groups.To analyze the differences between infant and childhood T-ALL samples on an epigenetic level, we performed miRNA sequencing and found 55 miRNAs which were differentially expressed between infant and childhood cases. Correlation analysis for differentially expressed miRNA-mRNA target pairs revealed 34 miRNA-mRNA pairs (Spearman’s Rho ≤ -0.6, FDR ≤ 0.05).Pathway analyses (Ingenuity Pathway Analysis/IPA, Qiagen) showed 51 pathways which were differentially regulated between infant and childhood patients (p-value < 0.05). Most perturbed pathways fell into categories with functions in the immune system or were cancer-related, including differentiation, proliferation, apoptosis or cell survival signaling. Examples include ERK5 and TLR signaling. Both toll-like-receptors 2 (TLR2) and 4 (TLR4) were predicted to be inhibited by IPA leading to an aberrant expression of their downstream targets. TLR2 was not significantly downregulated in T-ALL infant samples with a logFC of -1.21 (FDR = 0.5), because of variant expressions within the groups. However, one infant case showing a slightly higher expression of TLR2 was carrying an SNV in its coding sequence leading to a missense variant. Several TLR2 targets including SELP, ITGA2B, IL1B, CXCL8 and CD86 were significantly downregulated in infant compared to childhood T-ALL samples.
Conclusion
Our analyses on exome, transcriptome and miRnome level suggests that infant T-ALL has distinct disease features compared to childhood T-ALL. Differences were observed on both transcriptomic and epigenetic level. Moreover, we describe several differentially expressed pathways including ERK5 and TLR signaling pathways.
Session topic: E-poster
Keyword(s): Infant, Mutation analysis, T cell acute lymphoblastic leukemia
Type: Eposter Presentation
Background
Survival rates of infants (< 1 year of age) diagnosed with acute lymphoblastic leukemia (ALL) remain poor with a 4-year event free survival of 47% (Interfant-99). Beside their often highly aggressive initial clinical presentation, these patients usually do not respond well to current therapies. For reasons not yet understood, nearly all of those patients present with B cell-ALL with T cell-ALL remaining an absolute rarity in infants.
Aims
Given its rarity, the biology of infant T-ALL is not understood. Also, it is not clear whether it presents a distinct disease compared to T-ALL diagnosed in later childhood. The aim of our present study therefore was to identify the landscape of genetic alterations of infant T-ALL by whole-exome sequencing (WES), transcriptome and microRNA sequencing.
Methods
We analyzed a total of three infant T-ALL patients and six childhood T-ALL patients as comparison. All sequencing was performed on a HiSeq 2500 (Illumina). Obtained sequence reads were aligned to the human reference genome. Resulting variation calls were annotated by Variant Effect Predictor. MuTect and VarScan2 were employed for identification of somatic nucleotide variations (SNVs). Correlation analyses based on public databases for miRNA-mRNA targeting were performed to reveal miRNA-mRNA pairs expressed in a negative correlation fashion.
Results
In total, 4504 genes had SNVs in any of the three infant patients, 1305 were recurrent in at least two and 557 in all three infant patients. We did not detect any SNVs in Notch1, however, we found SNVs in Notch2 and Notch3. On transcriptome level, 676 genes were differentially expressed (│logFC│ ≥ 1, FDR < 0.05) between the patient groups. Out of these genes, 194 were downregulated in infants and 482 were upregulated when compared to childhood cases. The hierarchical clustering of these significantly differentially expressed genes clearly separated the two patient groups.To analyze the differences between infant and childhood T-ALL samples on an epigenetic level, we performed miRNA sequencing and found 55 miRNAs which were differentially expressed between infant and childhood cases. Correlation analysis for differentially expressed miRNA-mRNA target pairs revealed 34 miRNA-mRNA pairs (Spearman’s Rho ≤ -0.6, FDR ≤ 0.05).Pathway analyses (Ingenuity Pathway Analysis/IPA, Qiagen) showed 51 pathways which were differentially regulated between infant and childhood patients (p-value < 0.05). Most perturbed pathways fell into categories with functions in the immune system or were cancer-related, including differentiation, proliferation, apoptosis or cell survival signaling. Examples include ERK5 and TLR signaling. Both toll-like-receptors 2 (TLR2) and 4 (TLR4) were predicted to be inhibited by IPA leading to an aberrant expression of their downstream targets. TLR2 was not significantly downregulated in T-ALL infant samples with a logFC of -1.21 (FDR = 0.5), because of variant expressions within the groups. However, one infant case showing a slightly higher expression of TLR2 was carrying an SNV in its coding sequence leading to a missense variant. Several TLR2 targets including SELP, ITGA2B, IL1B, CXCL8 and CD86 were significantly downregulated in infant compared to childhood T-ALL samples.
Conclusion
Our analyses on exome, transcriptome and miRnome level suggests that infant T-ALL has distinct disease features compared to childhood T-ALL. Differences were observed on both transcriptomic and epigenetic level. Moreover, we describe several differentially expressed pathways including ERK5 and TLR signaling pathways.
Session topic: E-poster
Keyword(s): Infant, Mutation analysis, T cell acute lymphoblastic leukemia
Abstract: E844
Type: Eposter Presentation
Background
Survival rates of infants (< 1 year of age) diagnosed with acute lymphoblastic leukemia (ALL) remain poor with a 4-year event free survival of 47% (Interfant-99). Beside their often highly aggressive initial clinical presentation, these patients usually do not respond well to current therapies. For reasons not yet understood, nearly all of those patients present with B cell-ALL with T cell-ALL remaining an absolute rarity in infants.
Aims
Given its rarity, the biology of infant T-ALL is not understood. Also, it is not clear whether it presents a distinct disease compared to T-ALL diagnosed in later childhood. The aim of our present study therefore was to identify the landscape of genetic alterations of infant T-ALL by whole-exome sequencing (WES), transcriptome and microRNA sequencing.
Methods
We analyzed a total of three infant T-ALL patients and six childhood T-ALL patients as comparison. All sequencing was performed on a HiSeq 2500 (Illumina). Obtained sequence reads were aligned to the human reference genome. Resulting variation calls were annotated by Variant Effect Predictor. MuTect and VarScan2 were employed for identification of somatic nucleotide variations (SNVs). Correlation analyses based on public databases for miRNA-mRNA targeting were performed to reveal miRNA-mRNA pairs expressed in a negative correlation fashion.
Results
In total, 4504 genes had SNVs in any of the three infant patients, 1305 were recurrent in at least two and 557 in all three infant patients. We did not detect any SNVs in Notch1, however, we found SNVs in Notch2 and Notch3. On transcriptome level, 676 genes were differentially expressed (│logFC│ ≥ 1, FDR < 0.05) between the patient groups. Out of these genes, 194 were downregulated in infants and 482 were upregulated when compared to childhood cases. The hierarchical clustering of these significantly differentially expressed genes clearly separated the two patient groups.To analyze the differences between infant and childhood T-ALL samples on an epigenetic level, we performed miRNA sequencing and found 55 miRNAs which were differentially expressed between infant and childhood cases. Correlation analysis for differentially expressed miRNA-mRNA target pairs revealed 34 miRNA-mRNA pairs (Spearman’s Rho ≤ -0.6, FDR ≤ 0.05).Pathway analyses (Ingenuity Pathway Analysis/IPA, Qiagen) showed 51 pathways which were differentially regulated between infant and childhood patients (p-value < 0.05). Most perturbed pathways fell into categories with functions in the immune system or were cancer-related, including differentiation, proliferation, apoptosis or cell survival signaling. Examples include ERK5 and TLR signaling. Both toll-like-receptors 2 (TLR2) and 4 (TLR4) were predicted to be inhibited by IPA leading to an aberrant expression of their downstream targets. TLR2 was not significantly downregulated in T-ALL infant samples with a logFC of -1.21 (FDR = 0.5), because of variant expressions within the groups. However, one infant case showing a slightly higher expression of TLR2 was carrying an SNV in its coding sequence leading to a missense variant. Several TLR2 targets including SELP, ITGA2B, IL1B, CXCL8 and CD86 were significantly downregulated in infant compared to childhood T-ALL samples.
Conclusion
Our analyses on exome, transcriptome and miRnome level suggests that infant T-ALL has distinct disease features compared to childhood T-ALL. Differences were observed on both transcriptomic and epigenetic level. Moreover, we describe several differentially expressed pathways including ERK5 and TLR signaling pathways.
Session topic: E-poster
Keyword(s): Infant, Mutation analysis, T cell acute lymphoblastic leukemia
Type: Eposter Presentation
Background
Survival rates of infants (< 1 year of age) diagnosed with acute lymphoblastic leukemia (ALL) remain poor with a 4-year event free survival of 47% (Interfant-99). Beside their often highly aggressive initial clinical presentation, these patients usually do not respond well to current therapies. For reasons not yet understood, nearly all of those patients present with B cell-ALL with T cell-ALL remaining an absolute rarity in infants.
Aims
Given its rarity, the biology of infant T-ALL is not understood. Also, it is not clear whether it presents a distinct disease compared to T-ALL diagnosed in later childhood. The aim of our present study therefore was to identify the landscape of genetic alterations of infant T-ALL by whole-exome sequencing (WES), transcriptome and microRNA sequencing.
Methods
We analyzed a total of three infant T-ALL patients and six childhood T-ALL patients as comparison. All sequencing was performed on a HiSeq 2500 (Illumina). Obtained sequence reads were aligned to the human reference genome. Resulting variation calls were annotated by Variant Effect Predictor. MuTect and VarScan2 were employed for identification of somatic nucleotide variations (SNVs). Correlation analyses based on public databases for miRNA-mRNA targeting were performed to reveal miRNA-mRNA pairs expressed in a negative correlation fashion.
Results
In total, 4504 genes had SNVs in any of the three infant patients, 1305 were recurrent in at least two and 557 in all three infant patients. We did not detect any SNVs in Notch1, however, we found SNVs in Notch2 and Notch3. On transcriptome level, 676 genes were differentially expressed (│logFC│ ≥ 1, FDR < 0.05) between the patient groups. Out of these genes, 194 were downregulated in infants and 482 were upregulated when compared to childhood cases. The hierarchical clustering of these significantly differentially expressed genes clearly separated the two patient groups.To analyze the differences between infant and childhood T-ALL samples on an epigenetic level, we performed miRNA sequencing and found 55 miRNAs which were differentially expressed between infant and childhood cases. Correlation analysis for differentially expressed miRNA-mRNA target pairs revealed 34 miRNA-mRNA pairs (Spearman’s Rho ≤ -0.6, FDR ≤ 0.05).Pathway analyses (Ingenuity Pathway Analysis/IPA, Qiagen) showed 51 pathways which were differentially regulated between infant and childhood patients (p-value < 0.05). Most perturbed pathways fell into categories with functions in the immune system or were cancer-related, including differentiation, proliferation, apoptosis or cell survival signaling. Examples include ERK5 and TLR signaling. Both toll-like-receptors 2 (TLR2) and 4 (TLR4) were predicted to be inhibited by IPA leading to an aberrant expression of their downstream targets. TLR2 was not significantly downregulated in T-ALL infant samples with a logFC of -1.21 (FDR = 0.5), because of variant expressions within the groups. However, one infant case showing a slightly higher expression of TLR2 was carrying an SNV in its coding sequence leading to a missense variant. Several TLR2 targets including SELP, ITGA2B, IL1B, CXCL8 and CD86 were significantly downregulated in infant compared to childhood T-ALL samples.
Conclusion
Our analyses on exome, transcriptome and miRnome level suggests that infant T-ALL has distinct disease features compared to childhood T-ALL. Differences were observed on both transcriptomic and epigenetic level. Moreover, we describe several differentially expressed pathways including ERK5 and TLR signaling pathways.
Session topic: E-poster
Keyword(s): Infant, Mutation analysis, T cell acute lymphoblastic leukemia
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