The leukemogenic TCF3-HLF fusion deregulates super-enhancers including a critical activation site conferring MYC transcriptional dependency
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ABSTRACT:
PROVIDER: PRJEB27179 | ENA |
REPOSITORIES: ENA
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Project description:Oncogenic chimeric transcription factors are central drivers in cancer. To understand how the TCF3-HLF fusion protein rewires the transcriptional landscape in t(17;19) positive leukemia, functional genetic and proteomic experiments were conducted. In this dataset, the protein-protein interactions of the endogenous TCF3-HLF complex were characterized by AP-MS.
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Project description:The TCF3-HLF translocation is a very rare rearrangement in ALL that is associated with an extremely poor prognosis. The TCF3-HLF fusion gene in the described case resulted in the fusion of the homeobox-related gene of TCF3 to the leucine zipper domain of HLF. The TCF3-HLF fusion gene product acts as a transcriptional factor leading to the dedifferentiation of mature B lymphocytes into an immature state (lymphoid stem cells). This process initiates the formation of pre-leukaemic cells. Due to the rarity of this chromosomal aberration, only a few cases have been described in the literature. The advantage of this work is the presentation of an interesting case of clonal evolution of cancer cells and the cumulative implications (diagnostic and prognostic) of the patient’s genetic alterations.
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Project description:Despite improved 5-year overall survival rates in B-cell acute lymphoblastic leukemia (B-ALL) due to therapy escalation, effective treatments for relapsed and treatment-resistant disease, especially in specific subtypes like those with TCF3 (formerly E2A) fusions, remain scarce. TCF3, a key regulator of B-cell development, is implicated in various chromosomal translocations linked to lymphoid malignancies, such as TCF3::PBX1 fusion (5% of pediatric B-ALL) and TCF3::HLF fusion (~0.5% of pediatric B-ALL). Current omics research predominantly relies on transcriptomics, but it's increasingly recognized that this may not adequately reflect protein expression, the main targets of drugs and functional entities in biological processes. This study comprehensively analyzed proteomic landscapes of TCF3::HLF+ (n=6) and TCF3::PBX1+ (n=5) B-ALL using primary patient-derived xenografts (PDX), liquid chromatography tandem mass spectrometry, and data-dependent acquisition.
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Project description:Developmental transcription factors act in networks, but how these networks achieve cell- and tissue specificity is still poorly understood. Here we explored pre-B cell leukemia homeobox 1 (PBX1) in adult neurogenesis combining genomic, transcriptomic, and proteomic approaches. ChIP-Seq analysis uncovered PBX1 binding to a wide range of different sites. Integration of PBX1 ChIP-seq with ATAC-seq data predicted interaction partners, which were subsequently validated by mass spectrometry. Spatial transcriptomics revealed distinct temporal expression dynamics of Pbx1 and interacting factors. Among these were class I bHLH proteins TCF3, TCF4 and TCF12. RNA-seq upon Pbx1, Tcf3 and Tcf4 knockdown identified proliferation- and differentiation associated genes as shared targets. Neuronal differentiation was reduced upon depletion of either factor, suggesting functional cooperation between PBX1 and TCF3/4. Notably, while physiological PBX1-TCF interactions have not yet been described, chromosomal translocation resulting in genomic TCF3::PBX1 fusion characterizes a subtype of acute lymphoblastic leukemia. Introducing Pbx1 into Nalm6 cells, a pre-B cell line expressing TCF3 but lacking PBX1, upregulated leukemogenic genes including BLK and NOTCH3, arguing that functional PBX1-TCF cooperation likely extends to hematopoietic contexts. Our study hence uncovers a PBX1-TCF module orchestrating the balance between progenitor cell proliferation and differentiation in adult neurogenesis with implications for leukemia etiology.
2024-09-16 | GSE248755 | GEO
Project description:The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signaling suggested Tcf3 should activate target genes in response to Wnts, here we show that Wnt3a and Tcf3 effectively antagonize each other’s effects on gene expression. Genetic ablation of Tcf3 caused similar effects as treating cells with recombinant Wnt3a. Moreover, Tcf3 was not necessary for Wnt3a-stimulation of gene expression as the majority of Wnt3a-stimulated genes exhibited a greater increase in Tcf3-/- ES cells than in Tcf3+/+ ES cells. These expression data, together with genetic experiments, show that Wnt3a stimulates ES cell self renewal by inhibiting Tcf3. Tcf3+/+ and Tcf3-/- mouse embryonic stem cells were cultured in self renewal conditions containing recombinant Wnt3a for RNA extraction and hybridization on Affymetrix microarrays.
2011-02-24 | E-GEOD-27455 | biostudies-arrayexpress
Project description:The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signaling suggested Tcf3 should activate target genes in response to Wnts, here we show that Wnt3a and Tcf3 effectively antagonize each other’s effects on gene expression. Genetic ablation of Tcf3 caused similar effects as treating cells with recombinant Wnt3a. Moreover, Tcf3 was not necessary for Wnt3a-stimulation of gene expression as the majority of Wnt3a-stimulated genes exhibited a greater increase in Tcf3-/- ES cells than in Tcf3+/+ ES cells. These expression data, together with genetic experiments, show that Wnt3a stimulates ES cell self renewal by inhibiting Tcf3.
2011-02-24 | GSE27455 | GEO
Project description:The pathogenesis of MLL-fusion gene leukemias has been linked to upregulated expression of HOX genes and of the HOX-cofactor Meis1.The functions of the HOX/MEIS1 complex in leukemia however remain unclear. Here, we used inducible MEIS1-knockout mice coupled with MLL-AF9 knockin mice to decipher the role of MEIS1 in leukemia. We found that MEIS1 was critically required for established leukemia. Further, MEIS1 loss led to increased oxygen flux and apoptosis, while hypoxia reversed these effects. Finally, we identify HLF as a downstream mediator of MEIS1 in leukemia. Overexpression of HLF prevents oxygen flux and rescues the leukemia phenotype in MEIS1-deficient cells. Thus, the oncogenic effects of MEIS1 are at least partly mediated by an HLF-driven hypoxic state.
2015-05-21 | GSE58732 | GEO
Project description:YAP/TAZ-dependent expression of lncRNAs [HLF]
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Project description:Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem (ES) cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells, while repressing another distinct target subset. In the normal mouse mammary gland Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer.
2012-10-23 | GSE38893 | GEO