COMPARATIVE ANALYSIS OF GENE REGULATORY NETWORKS IN LYMPHOID LEUKEMIAS USING THE INTERACTIVE HEMAP RESOURCE
(Abstract release date: 05/19/16)
EHA Library. Mehtonen J. 06/10/16; 133138; P150
Juha Mehtonen
Contributions
Contributions
Abstract
Abstract: P150
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Acute lymphoblastic leukemia (ALL) is a paradigmatic example of a disease that can develop at an early age as a result of genetic lesions that impede lineage commitment. In normal development, cells commit to their lineage and differentiated phenotype state by the activation of transcription factors (TFs), or TF modules, in a series of decision points at which a choice is made between alternative lineage fates. In parallel, epigenetic regulation has emerged as an important mechanism that can corrupt the gene regulatory network.
Aims
We set out to examine whether patient expression profiles could be used to quantitatively detect the blocks to differentiation and to reveal aberrantly active TF loci. We further evaluated how amenable lymphoblastic leukemia cases may be to treatment with drugs acting on epigenetic modifiers.
Methods
We analyzed 1,304 pre-B-ALL, 385 T-ALL and 801 B-CLL transcriptomes as part of a curated set of 9,544 transcriptomes collected across 36 hematological malignancies to facilitate the characterization of mechanisms that can corrupt the regulatory network in lymphoblastic leukemias. Sample similarity was assessed using t-Distributed Stochastic Neighbor Embedding (t-SNE) maps that permitted detecting changes in gene expression at subtype resolution and association with specific TF translocations, epigenetic changes and aberrant enhancers. The expression of genes that encode epigenetic modifiers with existing small molecule drugs (list from ChEMBL) was compared between ALL and chronic lymphoblastic leukemia (CLL) and other hematological malignancies.
Results
We scored gene sets of blood cell type lineage-determining TFs across the transcriptome dataset and found that cancer samples lack the characteristic mutually exclusive lineage-restricted pattern of these TF sets. Analysis of stem cell similarity revealed predominant expression of a subset of hematopoietic stem cell TFs across all acute leukemias. Of these, ERG expression was highest in pre-B-ALL and correlated with high activity of a super-enhancer based on DNAse hypersensitivity and enhancer RNA expression. In addition, we found disease cluster-specific activation of transcription-regulating gene loci with low or undetectable expression in normal blood cell types. In the cluster of the common pre-B-ALL subtype carrying the t12;21 translocation (ETV6-RUNX1 fusion), four TFs (IRX1, MYOCD, NR3C2 and SOX11) had a subtype-specific elevated expression level. We validated with overexpression and silencing of ETV6-RUNX1 that the observed upregulation of IRX1 occurs downstream of the fusion TF. Furthermore, high expression of epigenetic modifiers with existing small molecule drugs (available from ChEMBL) was significantly enriched in CLL, T-ALL, one pre-B-ALL and one AML cluster among the 9,544 hematological samples.
Conclusion
We demonstrate that there are recurrent patterns of aberrant TF expression in leukemia disease clusters. Misregulated expression of ERG in pre-B-ALL appears to be mediated by a stem cell super-enhancer based on the deep sequencing results presented. Moreover, elevated expression of drug targets that function as epigenetic modifiers was enriched in specific leukemia clusters. Their inhibition potentially restores expression of a larger repertoire of misregulated genes. Particularly in CLL, these genes represent promising treatment targets for the reconditioning of blast cells.
Session topic: Acute lymphoblastic leukemia - Biology 1
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Acute lymphoblastic leukemia (ALL) is a paradigmatic example of a disease that can develop at an early age as a result of genetic lesions that impede lineage commitment. In normal development, cells commit to their lineage and differentiated phenotype state by the activation of transcription factors (TFs), or TF modules, in a series of decision points at which a choice is made between alternative lineage fates. In parallel, epigenetic regulation has emerged as an important mechanism that can corrupt the gene regulatory network.
Aims
We set out to examine whether patient expression profiles could be used to quantitatively detect the blocks to differentiation and to reveal aberrantly active TF loci. We further evaluated how amenable lymphoblastic leukemia cases may be to treatment with drugs acting on epigenetic modifiers.
Methods
We analyzed 1,304 pre-B-ALL, 385 T-ALL and 801 B-CLL transcriptomes as part of a curated set of 9,544 transcriptomes collected across 36 hematological malignancies to facilitate the characterization of mechanisms that can corrupt the regulatory network in lymphoblastic leukemias. Sample similarity was assessed using t-Distributed Stochastic Neighbor Embedding (t-SNE) maps that permitted detecting changes in gene expression at subtype resolution and association with specific TF translocations, epigenetic changes and aberrant enhancers. The expression of genes that encode epigenetic modifiers with existing small molecule drugs (list from ChEMBL) was compared between ALL and chronic lymphoblastic leukemia (CLL) and other hematological malignancies.
Results
We scored gene sets of blood cell type lineage-determining TFs across the transcriptome dataset and found that cancer samples lack the characteristic mutually exclusive lineage-restricted pattern of these TF sets. Analysis of stem cell similarity revealed predominant expression of a subset of hematopoietic stem cell TFs across all acute leukemias. Of these, ERG expression was highest in pre-B-ALL and correlated with high activity of a super-enhancer based on DNAse hypersensitivity and enhancer RNA expression. In addition, we found disease cluster-specific activation of transcription-regulating gene loci with low or undetectable expression in normal blood cell types. In the cluster of the common pre-B-ALL subtype carrying the t12;21 translocation (ETV6-RUNX1 fusion), four TFs (IRX1, MYOCD, NR3C2 and SOX11) had a subtype-specific elevated expression level. We validated with overexpression and silencing of ETV6-RUNX1 that the observed upregulation of IRX1 occurs downstream of the fusion TF. Furthermore, high expression of epigenetic modifiers with existing small molecule drugs (available from ChEMBL) was significantly enriched in CLL, T-ALL, one pre-B-ALL and one AML cluster among the 9,544 hematological samples.
Conclusion
We demonstrate that there are recurrent patterns of aberrant TF expression in leukemia disease clusters. Misregulated expression of ERG in pre-B-ALL appears to be mediated by a stem cell super-enhancer based on the deep sequencing results presented. Moreover, elevated expression of drug targets that function as epigenetic modifiers was enriched in specific leukemia clusters. Their inhibition potentially restores expression of a larger repertoire of misregulated genes. Particularly in CLL, these genes represent promising treatment targets for the reconditioning of blast cells.
Session topic: Acute lymphoblastic leukemia - Biology 1
Abstract: P150
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Acute lymphoblastic leukemia (ALL) is a paradigmatic example of a disease that can develop at an early age as a result of genetic lesions that impede lineage commitment. In normal development, cells commit to their lineage and differentiated phenotype state by the activation of transcription factors (TFs), or TF modules, in a series of decision points at which a choice is made between alternative lineage fates. In parallel, epigenetic regulation has emerged as an important mechanism that can corrupt the gene regulatory network.
Aims
We set out to examine whether patient expression profiles could be used to quantitatively detect the blocks to differentiation and to reveal aberrantly active TF loci. We further evaluated how amenable lymphoblastic leukemia cases may be to treatment with drugs acting on epigenetic modifiers.
Methods
We analyzed 1,304 pre-B-ALL, 385 T-ALL and 801 B-CLL transcriptomes as part of a curated set of 9,544 transcriptomes collected across 36 hematological malignancies to facilitate the characterization of mechanisms that can corrupt the regulatory network in lymphoblastic leukemias. Sample similarity was assessed using t-Distributed Stochastic Neighbor Embedding (t-SNE) maps that permitted detecting changes in gene expression at subtype resolution and association with specific TF translocations, epigenetic changes and aberrant enhancers. The expression of genes that encode epigenetic modifiers with existing small molecule drugs (list from ChEMBL) was compared between ALL and chronic lymphoblastic leukemia (CLL) and other hematological malignancies.
Results
We scored gene sets of blood cell type lineage-determining TFs across the transcriptome dataset and found that cancer samples lack the characteristic mutually exclusive lineage-restricted pattern of these TF sets. Analysis of stem cell similarity revealed predominant expression of a subset of hematopoietic stem cell TFs across all acute leukemias. Of these, ERG expression was highest in pre-B-ALL and correlated with high activity of a super-enhancer based on DNAse hypersensitivity and enhancer RNA expression. In addition, we found disease cluster-specific activation of transcription-regulating gene loci with low or undetectable expression in normal blood cell types. In the cluster of the common pre-B-ALL subtype carrying the t12;21 translocation (ETV6-RUNX1 fusion), four TFs (IRX1, MYOCD, NR3C2 and SOX11) had a subtype-specific elevated expression level. We validated with overexpression and silencing of ETV6-RUNX1 that the observed upregulation of IRX1 occurs downstream of the fusion TF. Furthermore, high expression of epigenetic modifiers with existing small molecule drugs (available from ChEMBL) was significantly enriched in CLL, T-ALL, one pre-B-ALL and one AML cluster among the 9,544 hematological samples.
Conclusion
We demonstrate that there are recurrent patterns of aberrant TF expression in leukemia disease clusters. Misregulated expression of ERG in pre-B-ALL appears to be mediated by a stem cell super-enhancer based on the deep sequencing results presented. Moreover, elevated expression of drug targets that function as epigenetic modifiers was enriched in specific leukemia clusters. Their inhibition potentially restores expression of a larger repertoire of misregulated genes. Particularly in CLL, these genes represent promising treatment targets for the reconditioning of blast cells.
Session topic: Acute lymphoblastic leukemia - Biology 1
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Acute lymphoblastic leukemia (ALL) is a paradigmatic example of a disease that can develop at an early age as a result of genetic lesions that impede lineage commitment. In normal development, cells commit to their lineage and differentiated phenotype state by the activation of transcription factors (TFs), or TF modules, in a series of decision points at which a choice is made between alternative lineage fates. In parallel, epigenetic regulation has emerged as an important mechanism that can corrupt the gene regulatory network.
Aims
We set out to examine whether patient expression profiles could be used to quantitatively detect the blocks to differentiation and to reveal aberrantly active TF loci. We further evaluated how amenable lymphoblastic leukemia cases may be to treatment with drugs acting on epigenetic modifiers.
Methods
We analyzed 1,304 pre-B-ALL, 385 T-ALL and 801 B-CLL transcriptomes as part of a curated set of 9,544 transcriptomes collected across 36 hematological malignancies to facilitate the characterization of mechanisms that can corrupt the regulatory network in lymphoblastic leukemias. Sample similarity was assessed using t-Distributed Stochastic Neighbor Embedding (t-SNE) maps that permitted detecting changes in gene expression at subtype resolution and association with specific TF translocations, epigenetic changes and aberrant enhancers. The expression of genes that encode epigenetic modifiers with existing small molecule drugs (list from ChEMBL) was compared between ALL and chronic lymphoblastic leukemia (CLL) and other hematological malignancies.
Results
We scored gene sets of blood cell type lineage-determining TFs across the transcriptome dataset and found that cancer samples lack the characteristic mutually exclusive lineage-restricted pattern of these TF sets. Analysis of stem cell similarity revealed predominant expression of a subset of hematopoietic stem cell TFs across all acute leukemias. Of these, ERG expression was highest in pre-B-ALL and correlated with high activity of a super-enhancer based on DNAse hypersensitivity and enhancer RNA expression. In addition, we found disease cluster-specific activation of transcription-regulating gene loci with low or undetectable expression in normal blood cell types. In the cluster of the common pre-B-ALL subtype carrying the t12;21 translocation (ETV6-RUNX1 fusion), four TFs (IRX1, MYOCD, NR3C2 and SOX11) had a subtype-specific elevated expression level. We validated with overexpression and silencing of ETV6-RUNX1 that the observed upregulation of IRX1 occurs downstream of the fusion TF. Furthermore, high expression of epigenetic modifiers with existing small molecule drugs (available from ChEMBL) was significantly enriched in CLL, T-ALL, one pre-B-ALL and one AML cluster among the 9,544 hematological samples.
Conclusion
We demonstrate that there are recurrent patterns of aberrant TF expression in leukemia disease clusters. Misregulated expression of ERG in pre-B-ALL appears to be mediated by a stem cell super-enhancer based on the deep sequencing results presented. Moreover, elevated expression of drug targets that function as epigenetic modifiers was enriched in specific leukemia clusters. Their inhibition potentially restores expression of a larger repertoire of misregulated genes. Particularly in CLL, these genes represent promising treatment targets for the reconditioning of blast cells.
Session topic: Acute lymphoblastic leukemia - Biology 1
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