Oncogene cooperation in human leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA940078 | ENA |
REPOSITORIES: ENA
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Project description:Validation of previously defined oncogene cooperativity signature across various human leukemia types. Additionaly, to characterize functional impact of these genes and defined network interactions that drive leukemia progression and survival.
2025-04-04 | GSE226372 | GEO
Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population. In three independent experiments bone marrow cells were transduced with MSCV-MN1-IRES/YFP or empty vector. 72h after transduction EYFP-positive cells were FACS-sorted and RNA isolated by ion-exchange chromatography with RNAmini (Qiagen) according to the manufacturerâs protocol
2010-04-08 | E-GEOD-13189 | biostudies-arrayexpress
Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population.
2009-06-01 | GSE13189 | GEO
Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.
2023-04-29 | GSE181759 | GEO
Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.
2023-04-29 | GSE182312 | GEO
Project description:Overexpression of the oncogene MEF2C opposes NOTCH signalling in T versus B lineage decision, driving leukemia in the thymus context
2022-05-14 | GSE160407 | GEO
Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.
2023-04-29 | GSE182316 | GEO
Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.
2023-04-29 | GSE182315 | GEO
Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.
2023-04-29 | GSE182313 | GEO
Project description:Analysis of Oncogenic Cooperation during Leukemia Progression by Single Cell RNA-seq
| PRJNA742078 | ENA