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Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques

ABSTRACT: In this study, we demonstrate that LAMP5 is essential for proliferation of MLL-rearranged leukemias. Through gene expression changes occurring upon LAMP5 knockdown, we show that LAMP5 maintains an important balance between Type I interferon and NFkB signaling, and that knockdown biases MLL leukemia cells towards activation of the interferon pathway

ORGANISM(S): Macaca mulatta

PROVIDER: GSE171669 | GEO | 2022/04/06

REPOSITORIES: GEO

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LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for MLL-rearranged acute leukemia

Project description:In this study, we demonstrate that LAMP5 is essential for proliferation of MLL-rearranged leukemias. Through gene expression changes occurring upon LAMP5 knockdown, we show that LAMP5 maintains an important balance between Type I interferon and NFkB signaling, and that knockdown biases MLL leukemia cells towards activation of the interferon pathway

2022-08-07 | GSE166523 | GEO

LAMP5-AS1 drives leukemia cell stemness in MLL leukemia

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

The Amniotic Fluid Proteome Changes Across Gestation in Humans and Rhesus Macaques

Project description:Amniotic fluid is a complex biological medium that offers mechanical protection and nutrition to the fetus, and also plays a key role in normal fetal growth, organogenesis, and potentially fetal programming. Amniotic fluid is also critically involved in longitudinally shaping the in utero milieu during pregnancy. Yet, the molecular mechanism of action by which amniotic fluid regulates fetal development is ill-defined partly due to an incomplete understanding of the evolving composition of the amniotic fluid proteome. Prior research consisting of cross-sectional studies suggests that the amniotic fluid proteome changes as pregnancy advances, yet longitudinal alterations have not been confirmed because repeated sampling is prohibitive in humans. We therefore performed serial amniocenteses at early, mid, and late gestational time-points within the same pregnancies in a rhesus macaque model. Longitudinally-collected rhesus amniotic fluid samples were paired with gestational-age matched cross-sectional human samples. Utilizing LC-MS/MS isobaric labeling quantitative proteomics, we demonstrate considerable cross-species similarity between the amniotic fluid proteomes and large scale gestational-age associated changes in protein content throughout pregnancy. This is the first study to establish a reference proteomic profile across gestation. This non-human primate model holds promise as a translational platform for amniotic fluid studies and to identify adversely affected pregnancies.

2023-10-24 | PXD043519 | Pride

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

Project description:In this study, we identify MBNL1 as a unique molecular vulnerability across MLL-rearranged leukemias. Through transcriptomic profiling and novel splicing analyses of MLL-rearranged leukemia cell lines following shRNA knockdown of MBNL1, we show that MBNL1 regulates alternative splicing (predominantly intron retention) of genes essential to MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.

2020-03-25 | GSE123441 | GEO

Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques.

Project description:BACKGROUND:Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized. METHODS:Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 107 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues. RESULTS:Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor. CONCLUSIONS:U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype.

| S-EPMC6392471 | biostudies-other

Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques

Project description:Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques

| PRJNA720538 | ENA

Quantitative cellular proteome analysis of Fetal- and Adult-Derived MLL-Rearranged Leukemia

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

Zinc finger protein 521 overexpression is a feature of MLL-rearranged acute myeloid leukemia and contributes to the maintenance of myeloid differentiation block

Project description:ZNF521 is a multiple zinc finger transcription factor previously identified because abundantly and selectively expressed in normal CD34+ hematopoietic stem and progenitor cells. From microarray datasets, aberrant expression of ZNF521 has been reported in both pediatric and adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. However, a proper validation of microarray data is lacking, likewise ZNF521 contribution in MLL-rearranged AML is still uncertain. In this study, we show that ZNF521 is significantly upregulated in MLL translocated AML patients from a large pediatric cohort, regardless of the type of MLL translocations such as MLL-AF9, MLL-ENL, MLL-AF10 and MLL-AF6 fusion genes. Our in vitro functional studies demonstrate that ZNF521 play a critical role in the maintenance of the undifferentiated state of MLL-rearranged cells. Furthermore, analysis of the ZNF521 gene promoter region shows that ZNF521 is a direct downstream target of both MLL-AF9 and MLL-ENL fusion proteins. Gene expression profiling of MLL-AF9-rearranged THP-1 cells after depletion of ZNF521 reveals correlation with several expression signatures including stem cell-like and MLL fusion dependent programs. These data suggest that MLL fusion proteins activate ZNF521 expression to maintain the undifferentiated state and contribute to leukemogenesis. ZNF521 is required to block differentiation in MLL-rearranged AML cells

2017-03-31 | GSE79110 | GEO

The HDAC inhibitor Panobinostat (LBH589) exerts in vivo anti-leukaemic activity against in MLL-rearranged Acute Lymphoblastic Leukaemia and involves the RNF20/RNF40/WAC – H2B ubiquitination axis

Project description:We demonstrate the in vivo efficacy of the histone deacetylase inhibitor Panobinostat (LHB589) against MLL-rearranged ALL using xenograft mouse models of MLL-rearranged ALL cell lines and primary patient cells. Panobinostat monotherapy showed strong anti-leukaemic effects, extending survival and reducing overall disease burden. Comprehensive molecular analyses in vitro showed the anti-leukaemic activity in MLL-rearranged ALL to involve depletion of H2B ubiquitination via suppression of the RNF20/RNF40/WAC E3 ligase complex.

2017-07-12 | GSE78234 | GEO

Genes regulated by Meis1 in murine Mll-AF9 leukemia cells

Project description:Leukemias with MLL-rearrangements are characterized by high expression of the homeo box gene MEIS1. In these studies, we knocked down Meis1 expression by shRNA lentivirus transduction in murine Mll-AF9 leukemia cells. Meis1 knockdown resulted in decreased proliferation and survival of murine Mll-AF9 leukemia cells. We also observed reduced clonogenic capacity and increased monocytic differentiation. The establishment of leukemia in transplant recipients was significantly delayed by Meis1 knockdown. Gene expression profiling of cells transduced with Meis1 shRNA showed reduced expression of genes associated with cell cycle entry and progression. shRNA mediated knockdown of MEIS1 in human MLL-fusion gene leukemia cell lines resulted in reduced cell growth. These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell cycle entry. Targeting MEIS1 may have therapeutic potential for treating leukemias expressing this transcription factor. Keywords: Gene expression

2008-12-23 | GSE14101 | GEO

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