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Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure [scRNA-seq]

ABSTRACT: We have developed a mouse model in order to characterize in vivo chemotherapy resistance depending on niche. Global transcriptomics and phospho-proteomics at the single-cell level elucidated novel mechanisms of chemotherapy resistance depending on microenvironment, which might be suitable for pharmacological therapies. Comparison of the transcriptional profile of GFP+-sorted E2A-PBX1/preBCR+ leukemia cells in different tissues (bone marrow, spinal cord, lymph nodes, spleen) and after treatment with conventional chemotherapies prednisolone, daunorubicin compared to control (DMSO).

ORGANISM(S): Mus musculus

PROVIDER: GSE233940 | GEO | 2024/09/20

REPOSITORIES: GEO

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Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure [Bulk RNA-seq]

Project description:We have developed a mouse model in order to characterize in vivo chemotherapy resistance depending on niche. Global transcriptomics and phospho-proteomics at the single-cell level elucidated novel mechanisms of chemotherapy resistance depending on microenvironment, which might be suitable for pharmacological therapies. Comparison of the transcriptional profile of GFP+-sorted E2A-PBX1/preBCR+ leukemia cells in different tissues (bone marrow, spinal cord, lymph nodes, spleen) and after treatment with conventional chemotherapies prednisolone, daunorubicin compared to control (DMSO).

2024-09-20 | GSE233937 | GEO

Microarray data of mouse primary E2A-PBX1 leukemia and preleukemia cells

Project description:Microarray data of mouse primary E2A-PBX1 leukemias and preleukemia cells were compared to wild-type B-cell progenitor cells Aberrant activation of signaling pathways has been linked to leukemogenesis, however, little is known about cell signaling perturbations induced by fusion transcription factors. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the chimeric fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) ALL. We describe here signaling network remodeling by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. E2A-PBX1 binds and activates the transcription of its target genes ZAP70, SYK and LCK, which encode kinases upstream of PLCγ2. Efficient shRNA-mediated depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise compound knockdown of ZAP70, SYK or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy. Inhibition of SYK, LCK and SFK with small molecule inhibitors, including dasatinib, was highly effective in reducing pPLCγ2 and inhibiting proliferation of preBCR+ leukemias in vitro and in vivo. Combination small molecule inhibition of SYK, LCK and SFK showed promising preclinical efficacy for preBCR+/E2A-PBX1+ leukemias. These studies demonstrate that E2A-PBX1 induces signaling pathway perturbations upstream of PLCγ2, which render leukemias amenable to targeted therapeutic inhibition.

2016-05-03 | GSE81010 | GEO

Global gene expression profile of CNS-infiltrating E2A-PBX1+/preBCR+ ALL cells

Project description:In order to elucidate mechanism of resistance to BTKi and dasatinib in CNS-infiltrating leukemia cells and to investigate the CNS homing of E2A-PBX1/preBCR+ ALL cells, we performed global transcriptome analysis by RNA sequencing. RNA was isolated from CNS-infiltrating cells from vehicle, dasatinib, ibrutinib, dasatinib + ibrutinib-treated mice

2024-03-15 | GSE221238 | GEO

Global gene expression profile of CNS-infiltrating E2A-PBX1+/preBCR+ ALL cells

Project description:Global gene expression profile of CNS-infiltrating E2A-PBX1+/preBCR+ ALL cells

| PRJNA913580 | ENA

Proteomic analysis of patient-derived xenograft samples from children with B-cell acute lymphoblastic leukemia harboring TCF3::PBX1 and TCF3::HLF translocations

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

Transcriptome profiling of human pre-B ALL cell line 697 upon PBX1 or TCF3 knockdown (RNA-seq)

Project description:RNA-seq was performed to observe the gene expression changes in 697 cells following shRNA-mediated knockdown of PBX Homeobox 1 (PBX1) or Transcription Factor 3 (TCF3/E2A), each with two shRNAs. Cells treated with scrambled control shRNA were used as controls.

2020-05-13 | E-MTAB-8179 | biostudies-arrayexpress

SNP arrays to detect copy number changes in t(1;19) E2A-PBX1 positive leukemias

Project description:The experiment was to detect the identity and range of copy number alterations in a subtype of childhood leukemia defined by t(1;19) translocaitons The data will be presented in the manuscript "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels

2013-11-23 | GSE52654 | GEO

Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-20 | GSE233941 | GEO

Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure

Project description:Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure

| PRJNA978609 | ENA

Genetic features of B-cell lymphoblastic lymphoma with TCF3-PBX1.

Project description:BackgroundLymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL.MethodsWES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed.ResultsKMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis.ConclusionIn this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.

| S-EPMC9458492 | biostudies-literature

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