A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA831190 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18901309.fastq.gz | Fastqsanger.gz | |||
| SRR18901310.fastq.gz | Fastqsanger.gz | |||
| SRR18901311.fastq.gz | Fastqsanger.gz | |||
| SRR18901312.fastq.gz | Fastqsanger.gz | |||
| SRR18901313.fastq.gz | Fastqsanger.gz |
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Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.
2018-05-25 | PXD009338 | Pride
Project description:Improving the poor prognosis of infant leukemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven pediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, Disulfiram, based on its efficient ablation of MLL fusion proteins. The consequences of drug-induced MLL-fusion inhibition was confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and CHIP-qPCR and CHIP-seq analysis. All statistical tests were two-sided. Drug-induced inhibition of MLL-fusion proteins by Disulfiram resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukemia progression in vivo. Mechanistically, Disulfiram abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukemic programs setup by the MLL-fusion protein. Disulfiram can directly inhibit MLL-fusion proteins and demonstrates antitumor activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly target the initiating oncogenic MLL-fusion protein.
2022-08-01 | GSE203203 | GEO
Project description:Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene result in fusion proteins which retain the N-terminal portion of MLL fused with one of more than 70 different fusion partners. The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL fusion proteins in a fusion partner independent manner. We have demonstrated that blocking the menin-MLL interaction using small molecule inhibitor inhibits oncogenic activity of different MLL fusion proteins according to a mechanism that is independent on the fusion partner.
2018-06-09 | GSE69740 | GEO
Project description:MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r have been suggested to be sufficient to drive transformation. However, despite the prenatal origin of MLL-r, the incidence of congenital leukemia is very low with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific RNA binding protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-express MLL-ENL and LIN28B, we investigated the impact of LIN28B on AML. We show that LIN28B impedes the progression of MLL-r AML through a compromised leukemia initiating cell activity and a suppression of MYB signaling. Mechanistically, rather than involving the well-studied Lin28B-let7 miR axis, we found that LIN28B directly bound MYBBP1A mRNA, a co-repressor of MYB, and that positively correlated with MYBBP1A protein levels. Overexpression of MYBBP1A in MLL-ENL driven leukemogenesis largely phenocopied the tumor suppressor effects of LIN28B. Thereby, our work proposes that the developmentally-restricted expression of LIN28B during fetal development provides a protection against MYB-dependent AML.
2023-02-08 | GSE201083 | GEO
Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.
2024-04-02 | PXD042249 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-04-27 | GSE201373 | GEO
Project description:Background: MLL (KMT2A)-EB1 (MAPRE1) fusion was identified in a patient with de novo pro-B acute lymphoblastic leukemia. To investigate the leukemogenesis of MLL-EB1 fusion, a retroviral transduction of MLL-EB1 to murine bone marrow cells was performed. A frequent MLL fusion, MLL-AF10(OM-LZ), was used as a positive control. Results: Two MLL-EB1 immortalized cell lines (ME1 and ME2G), and a MLL-AF10(OM-LZ) immortalized cell line (12G) were generated. Microarray results showed that many genes including Evi1 and Ets1 were differentially expressed in ME1/ME2G and 12G cell lines.
2017-06-02 | GSE82156 | GEO
Project description:Fusion of the N-terminus of the mixed-lineage-leukemia (MLL) gene with various partner genes drives acute lymphoblastic leukemia (ALL). Despite the fusion proteins sharing some common attributes, transcriptome heterogeneity of MLL-fusion ALL is observed and the underlying mechanism and biological consequences are unknown. We compared the genome-wide occupancy of MLL-Af4 and MLL-AF9 in human ALL cells expressing FLAG-tagged fusion proteins. Although both oncoproteins retain the same MLL N-terminal domains that mediate chromatin binding, the two fusion proteins displayed largely non-overlapping binding profiles, with MLL-AF9 showing preferential binding at repetitive elements. The binding specificity of each fusion protein was associated with differential global gene activation distinguishing the two ALLs. A subset of prednisolone response genes were among the differentially regulated targets, and the resistance related genes were specifically upregulated in MLL-Af4/AF4 cells. These studies provide evidence that distinct chromatin occupancy of different MLL-fusion proteins is one driving force for transcriptome heterogeneity of MLL-fusion ALL, which could potentially result in the disparate therapeutic outcome of the disease.
2018-04-30 | GSE103947 | GEO
Project description:MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations encode chimeric MLL fusions that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of the MLL fusion protein. By comparing patient-derived leukemic cell lines, we find that MLL fusion-bound genes are a small subset of that recognized by wild-type MLL. In an inducible MLL-ENL cellular model, binding of the MLL fusion protein and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL fusion-bound genes, only 12 demonstrate a significant increase in mRNA expression upon induction of the fusion protein. In addition to Hoxa9 and Meis1, this includes Eya1 and Six1 which comprise a heterodimeric transcription factor important in several developmental pathways. We show that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, our data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes. We explored an inducible MLL-ENL cellular model, which was obtained from Dr. Robert Slany (University Erlangen, Germany). We wished to examine the differential expressed genes that are bound by MLL wild type (No 4-OHT) and fusion (4-OHT) proteins, combinding the ChIP-chip data to explore the potential MLL fusion-regulated genes.
2011-04-28 | E-GEOD-24794 | biostudies-arrayexpress
Project description:Chromosomal translocations encoding the MLL-AF9 and MLL-ENL fusion transcription factors are prevalent in infant acute leukaemia and therapy-related leukaemia. In order to conditionally express the MLL-fusion oncogene in primary haematopoietic progenitor cells (HPC), retroviral delivery of the Tet-off expression system was used (Horton et al., Cancer Res, 2005). Treatment of the conditional cells with Doxycycline caused a decrease in MLL-AF9/ENL mRNA and protein expression, and resulted in terminal differentiation of the cells. By analysing global changes in gene expression after treatment of cells with Doxycycline we were able to identify a number of potential transcriptional target genes of the MLL-AF9 and MLL-ENL fusion oncogenes.
2014-12-01 | GSE59236 | GEO