Ectopic expression of the oncogene TLX3 in DN-like stage
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ABSTRACT:
PROVIDER: PRJNA637054 | ENA |
REPOSITORIES: ENA
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Project description:It is now well established that members of the homeobox gene family play a critical role in normal hematopoietic cell development and that their unbalanced or ectopic expression can lead to characteristic perturbations in haemopoiesis and the onset of leukaemia. TLX3 expression in human haematologic malignancies is exclusive to T-ALL, where it is almost universally associated with transformation of early cortical CD4+CD8+ DP thymocytes. investigated the impact of ectopic TLX3 expression on T cell development, and the initiating mechanisms of T-cell transformation leading to leukemia onset. Forced expression of TLX3 disrupted the thymic develoment at DN-like stage giving rise to immortalized preleukemic clones.
2021-01-31 | GSE151670 | GEO
Project description:ChIP-Seq to study the binding of TLX3 in the mouse cell line DN-TLX3
2021-04-27 | GSE173407 | GEO
Project description:ChIP-Seq targeting TLX3 in DN-TL3
| PRJNA725476 | ENA
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors caused by the accumulation of genetic aberrations. One fifth of T-ALL patients are characterized by the ectopic expression of the homeobox transcription factor TLX3, which is normally not expressed in hematopoietic cells. Strikingly, this TLX3 positive subgroup of T-ALL has a high frequency of FLT3 mutations. Co-expression of TLX3 and FLT3-ITD in ex vivo pro-T cells conferred IL7 independent growth, confirming that TLX3 expression and FLT3 signaling cooperate to transform T-cells and make them less dependent on extracellular signals. After inducing TLX3 expression for 24 hours in Pro-T cells, transducin-like enhancer of split 4 (Tle4) was detected to be downregulated. Interestingly, T-ALL patients also present a strongly decreased expression of TLE4 specific to TLX3 and TLX1 subtypes. Family members of the transcriptional corepressor TLE4 have been described to interact and thus, inhibit transcription factors, through their interaction with an Engrailed-homology 1 (Eh1) domain. Generation of a point mutation in the Eh1 domain present at the N-terminus of TLX3 allowed us to show that TLE4 has a repressive effect on TLX3 activity. Together, we propose a TLX3+FLT3-ITD Pro-T cell model and use this to illustrate that low expression levels of TLE4 are favourable for the oncogenic function of TLX3.
2023-09-16 | GSE241640 | 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 | 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 | GSE182313 | 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:Here we performed a ChIP-seq experiment for Tlx3 trancription factor on a sample of mouse embryonic dorsal spinal cord. The result is the generation of the genome-wide maps for Tlx3 binding to chromatin in dILB neurones of the developing dorsal horn.
2021-04-09 | E-MTAB-6974 | biostudies-arrayexpress