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TLX3 ex vivo model identifies TLE4 as a co-repressor in T-ALL

ABSTRACT: TLX3 ex vivo model identifies TLE4 as a co-repressor in T-ALL

PROVIDER: PRJNA1009029 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25756900.fastq.gz	Fastqsanger.gz
	SRR25756901.fastq.gz	Fastqsanger.gz
	SRR25756902.fastq.gz	Fastqsanger.gz
	SRR25756903.fastq.gz	Fastqsanger.gz
	SRR25756904.fastq.gz	Fastqsanger.gz

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TLX3 ex vivo model identifies TLE4 as a co-repressor in T-ALL

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

ChIP-Seq targeting TLX3 in DN-TL3

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Ectopic expression of the oncogene TLX3 in DN-like stage

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.

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Regulation of Tlx3 by Pax6 is required for the restricted expression of Chrnα3 in Cerebellar Granule Neuron progenitors during development

Project description:Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6-/-Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-α3 subunit (Chrnα3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD)

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Regulation of Tlx3 by Pax6 is required for the restricted expression of ChrnÎ±3 in Cerebellar Granule Neuron progenitors during development

Project description:Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6-/-Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-Î±3 subunit (ChrnÎ±3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD) Anterior and posterior lobes of PN7 mouse cerebellum were isolated separately and differentially expressed genes were identified.

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ChIP-Seq targeting TLX3 in DN-TL3

Project description:ChIP-Seq targeting TLX3 in DN-TL3

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