LAMP5-AS1 drives leukemia cell stemness in MLL leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632553 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11784379_1.fastq.gz | Fastqsanger.gz | |||
| SRR11784379_2.fastq.gz | Fastqsanger.gz | |||
| SRR11784380_1.fastq.gz | Fastqsanger.gz | |||
| SRR11784380_2.fastq.gz | Fastqsanger.gz | |||
| SRR11784381_1.fastq.gz | Fastqsanger.gz |
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Project description:Mixed lineage leukemia (MLL) gene rearrangements trigger aberrant epigenetic modification and gene expression in hematopoietic stem and progenitor cells, which generates one of the most aggressive subtypes of leukemia with an apex self-renewal. It remains a challenge to directly inhibit rearranged MLL itself because of its multiple fusion partners and the poorly annotated downstream genes of MLL fusion proteins; therefore, novel therapeutic targets are urgently needed. We discovered that a long noncoding RNA (lncRNA) LAMP5-AS1 can promote higher degrees of H3K79 methylation, followed by upregulated expression of the self-renewal genes in the HOXA cluster, which are responsible for leukemia stemness in context of MLL rearrangements. Mechanistically, LAMP5-AS1 facilitated the methyltransferase activity of DOT1L by directly binding its Lys-rich region of catalytic domain, thus promoting the global patterns of H3K79 dimethylation and trimethylation in cells. These observations supported that LAMP5-AS1 upregulated H3K79me2/me3 and the transcription of DOT1L ectopic target genes. This is the first study that a lncRNA regulates the self-renewal program and differentiation block in MLL leukemia cells by facilitating the methyltransferase activity of DOT1L and global H3K79 methylation, showing its potential as a therapeutic target for MLL leukemia.
2021-08-01 | GSE150483 | GEO
Project description:Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of AML. Here, we demonstrated that Rictor is essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs. To understand the critical molecular events caused by Rictor loss in MLL-AF9-driven leukemia,the K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MA9_R1,MA9_R2,MA9_R3) or control(MA9_C1,MA9_C2,MA9_C3), and subjected to microarray analysis on Affymetrix microarrays.Furthermore, the MLL-NRIP3-driven mice model was chosen for further examination.The K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MN3_R1,MN3_R2,MN3_R3) or control(MN3_C1,MN3_C2,MN3_C3), and subjected to microarray analysis on Affymetrix microarrays.
2016-07-19 | E-GEOD-84505 | biostudies-arrayexpress
Project description:Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of AML. Here, we demonstrated that Rictor is essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs.
2016-07-19 | GSE84505 | GEO
Project description:BackgroundMixed-lineage leukemia (MLL) gene rearrangements trigger aberrant epigenetic modification and gene expression in hematopoietic stem and progenitor cells, which generates one of the most aggressive subtypes of leukemia with an apex self-renewal. It remains a challenge to directly inhibit rearranged MLL itself because of its multiple fusion partners and the poorly annotated downstream genes of MLL fusion proteins; therefore, novel therapeutic targets are urgently needed.MethodsqRT-PCR, receiver operating characteristic (ROC), and leukemia-free survival analysis were used to validate LAMP5-AS1 (LAMP5 antisense 1) expression and evaluate its clinical value. We performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5-AS1 in MLL leukemia progression and leukemia cell stemness. RNA electrophoretic mobility shift assays (EMSA), histone methyltransferase assay, RNA pull-down assay, and RNA fluorescence in situ hybridization (FISH) were used to validate the relationship between LAMP5-AS1 and the methyltransferase activity of DOT1L. The downstream ectopic target genes of LAMP5-AS1/DOT1L were validated by the chromatin immunoprecipitation (ChIP) and western blot.ResultsWe discovered that a long noncoding RNA (lncRNA) LAMP5-AS1 can promote higher degrees of H3K79 methylation, followed by upregulated expression of the self-renewal genes in the HOXA cluster, which are responsible for leukemia stemness in context of MLL rearrangements. We found that LAMP5-AS1 is specifically overexpressed in MLL leukemia patients (n = 58) than that in the MLL-wt leukemia (n = 163) (p < 0.001), and the patients with a higher expression level of LAMP5-AS1 exhibited a reduced 5-year leukemia-free survival (p < 0.01). LAMP5-AS1 suppression significantly reduced colony formation and increased differentiation of primary MLL leukemia CD34+ cells. Mechanistically, LAMP5-AS1 facilitated the methyltransferase activity of DOT1L by directly binding its Lys-rich region of catalytic domain, thus promoting the global patterns of H3K79 dimethylation and trimethylation in cells. These observations supported that LAMP5-AS1 upregulated H3K79me2/me3 and the transcription of DOT1L ectopic target genes.ConclusionsThis is the first study that a lncRNA regulates the self-renewal program and differentiation block in MLL leukemia cells by facilitating the methyltransferase activity of DOT1L and global H3K79 methylation, showing its potential as a therapeutic target for MLL leukemia.
| S-EPMC7302350 | biostudies-literature
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:The dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia
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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:How the stemness of adult stem cells and cancer stem cells is regulated by environmental cues through surface receptors is poorly understood. In this gene expression analysis, we found that, in the mouse MLL-AF9 acute myeloid leukemia (AML) model, a deficiency in intracellular signaling of inhibitory receptor PIR-B resulted in increased differentiation and decreased stemness of leukemia stem cells, revealing that PIR-B supports leukemia development. Our study indicates unexpected functional significance of a classical immune inhibitory receptor in the maintenance of stemness of cancer stem cells. Total RNA obtained from wild-type MLL-AF9 LSCs compared to PirBTM MLL-AF9 LSCs
2012-03-08 | E-GEOD-36329 | biostudies-arrayexpress
Project description:Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.
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Project description:The dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia [ribomethseq_primary_samples]
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