Unstranded RNA sequencing data
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228296 | GEO | 2024/01/18
REPOSITORIES: GEO
Similar Datasets
Project description:We applied CRISPR gene-editing to induce t(4;11) chromosomal translocations in primary human umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPCs) to faithfully model leukemias with the KMT2A-AFF1 fusion gene. We then performed gene expression profiling analysis using data obtained from RNA-seq of different primary cells and human cell lines.
2024-01-18 | GSE228237 | GEO
Project description:Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) produce KMT2A fusion proteins such as KMT2A-AFF1 (also known as MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 is thought to drive leukemogenesis through direct binding and inducing aberrant overexpression of key gene targets, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC. However, studying direct binding alone doesn’t allow for network generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified an KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1 driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.
2021-05-23 | GSE151386 | GEO
Project description:Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) produce KMT2A fusion proteins such as KMT2A-AFF1 (also known as MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 is thought to drive leukemogenesis through direct binding and inducing aberrant overexpression of key gene targets, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC. However, studying direct binding alone doesn’t allow for network generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified an KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1 driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.
2021-05-23 | GSE151389 | GEO
Project description:Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) produce KMT2A fusion proteins such as KMT2A-AFF1 (also known as MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 is thought to drive leukemogenesis through direct binding and inducing aberrant overexpression of key gene targets, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC. However, studying direct binding alone doesn’t allow for network generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified an KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1 driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.
2021-05-23 | GSE151385 | GEO
Project description:Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the Mixed Lineage Leukemia-1 gene, which encodes the KMT2A lysine methyltransferase. The most common translocations produce in-frame fusions of KMT2A to trans-activation domains of chromatin regulatory proteins. Here we develop a strategy to map the genome-wide occupancy of oncogenic KMT2A fusion proteins in primary patient samples regardless of fusion partner. By modifying the versatile CUT&Tag method for full automation we identify common and tumor-specific patterns of aberrant chromatin regulation induced by different KMT2A fusion proteins. Integration of automated and single-cell CUT&Tag uncovers lineage heterogeneity within patient samples and provides an attractive avenue for future diagnostics.
2021-06-10 | GSE159608 | GEO
Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.
2023-09-27 | GSE230806 | GEO
Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.
2023-09-27 | GSE230799 | GEO
Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.
2023-09-27 | GSE230791 | GEO
Project description:Chromosomal translocations involving the Lysine-Methyl-Tansferase-2A (KMT2A) locus generate potent oncogenes that cause highly aggressive acute leukemias KMT2A and the most frequent translocation partners encode proteins that interact with DNA to regulate developmental gene expression. KMT2A-oncogenic fusion proteins (oncoproteins) contribute to the epigenetic mechanisms that allow KMT2A-rearranged leukemias to evade targeted therapies. By profiling the oncoprotein-target sites of 34 KMT2A-rearranged leukemia samples, we find that the genomic enrichment of oncoprotein binding is highly variable between samples. At high levels of expression, the oncoproteins preferentially activate either the lymphoid or myeloid lineage program depending on the fusion partner. These fusion-partner-dependent binding sites correspond to the frequencies of each mutation in acute lymphoid leukemia versus acute myeloid leukemia. By profiling a sample that underwent a lymphoid-to-myeloid lineage switching event in response to lymphoid-directed treatment, we find the global oncoprotein levels are reduced and the oncoprotein-target gene network changes. At lower levels of expression, the oncoprotein shifts to a non-canonical regulatory program that favors the myeloid lineage, and in a subset of resistant patients, the Menin inhibitor Revumenib induces a similar response. The dynamic shifts in KMT2A oncoproteins we describe likely contribute to epigenetic resistance of KMT2A-rearranged leukemias to targeted therapies.
2024-09-27 | GSE252378 | GEO
Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, while the analysis of translocation-negative infant ALL remained unacknowledged. We generated and analyzed primary infant ALL expression profiles (n=73) typified by translocations t(4;11), t(11;19) and t(9;11), or the absence of MLL translocations, in order to study translocation-specific gene expression between the different genetic subtypes of infant ALL.
2009-12-15 | E-GEOD-19475 | biostudies-arrayexpress