ChIP-chip by SNP array of a case of a patient with TCF3-HLF-positive BCP-ALL
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PROVIDER: PRJNA613668 | ENA |
REPOSITORIES: ENA
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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.
2020-03-20 | GSE147280 | GEO
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.
2020-08-05 | PXD014992 | Pride
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.
2024-07-05 | PXD053677 | Pride
Project description:BackgroundThe use of high-throughput analytical techniques has enabled the description of acute lymphoblastic leukaemia (ALL) subtypes. 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.Case presentationThis work presents a patient with diagnosed with TCF3-HLF-positive ALL. Moreover, the additional genetic alterations, which play a key role in the pathogenesis of ALL, were detected in this patient: deletion of a fragment from the long arm of chromosome 13 (13q12.2-q21.1) containing the RB1 gene, intragenic deletions within the PAX5 gene and NOTCH1 intragenic duplication.ConclusionsA patient with coexistence of chromosomal alterations and the TCF3-HLF fusion has not yet been described. Identifying all these chromosomal aberrations at the time of diagnosis could be sufficient to determine the cumulative effects of the described deletions on the activity of other oncogenes or tumour suppressors, as well as on the clinical course of the disease. On the other hand, complex changes in the patient's karyotype and clonal evolution of cancer cells call into question the effectiveness of experimental therapy.
| S-EPMC7118981 | biostudies-literature
Project description:The leukemogenic TCF3-HLF fusion deregulates super-enhancers including a critical activation site conferring MYC transcriptional dependency
| PRJEB27179 | ENA
Project description:TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL while other drugs could be useful depending on the genetic context of individual patients.
| EGAS00001001876 | EGA
Project description:Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2D cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3D co-culture model combining human brain organoids and BCP-ALL cells. We noticed signicantly higher engraftment of TCF3::PBX1+ leukemia cell lines and patient-derived xenograft (PDX) cells in human induced pluripotent stem cell (iPSC)-derived cerebral organoids when compared to cell lines derived from chronic myeloid leukemia (CML), a subtype typically not associated with CNS involvement. Next, to validate translatability between organoid co-culture model and in vivo murine models, we confirmed that targeting CNS leukemia relevant pathways like CD79a/Igα or CXCR4-SDF1 reduced the invasion of BCP-ALL cells into organoids. RNA sequencing and further validations of organoid-invading leukemia cells compared to the non-invaded fraction revealed significant upregulation of the AP-1 transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in ALL-PDX cells recovered from the CNS compared to spleen blasts of mice transplanted with TCF3::PBX1+ PDX cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1-gene JUN in patients initially diagnosed as CNS-positive compared to CNS-negative cases as well as CNS-relapse cases in a cohort of 100 BCP-ALL patients. Our results suggest iPSC-derived brain organoids as a novel model to investigate CNS-involvement and identify the AP-1 pathway as a critical driver of CNS-disease in BCP-ALL.
2024-07-16 | GSE271998 | GEO
Project description:Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2D cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3D co-culture model combining human brain organoids and BCP-ALL-cells. We noticed significantly higher engraftment of BCP-ALL cell lines and patient-derived xenograft (PDX) cells in cerebral organoids as compared to non-ALL-cells. To validate translatability between organoid co-culture and in vivo murine models, we confirmed that targeting CNS leukemia relevant pathways like CD79a/Igα or CXCR4- SDF1 reduced the invasion of BCP-ALL-cells into organoids. RNA sequencing and functional validations of organoid-invading leukemia cells compared to the non-invaded fraction revealed significant upregulation of AP-1 transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in ALL-PDX-cells recovered from the CNS compared to spleen blasts of mice transplanted with TCF3::PBX1+ PDX-cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1-gene JUN in patients initially diagnosed as CNS-positive compared to CNS negative cases as well as CNS-relapse vs non-CNS-relapse cases in a cohort of 100 BCP-ALL-patients. Our results suggest CNS-organoids as a novel model to investigate CNS-involvement and identify the AP-1 pathway as a critical driver of CNS-disease in BCP-ALL.
2024-07-15 | GSE271750 | GEO
Project description:Primary xenografts were made from a variety of different high-risk childhood BCP-ALL leukemia samples.
2015-03-05 | GSE58290 | 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