LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for MLL-rearranged acute leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166523 | GEO | 2022/08/07
REPOSITORIES: GEO
Similar Datasets
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
2022-04-06 | GSE171669 | GEO
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
Project description:WIN Site inhibitors bind the WIN Site of WDR5 resulting in decreased transcription of WDR5 target genes, many of which encode components of the protein synthesis machinery. In this study, we determined proteome alterations in an MLL-rearranged leukemia cell line treated for either 24 or 72 hours with a WIN Site inhibitor. The data from these studies, along with Ribo-Seq, RNA-Seq, and CRISPR screen experiments, guided us in assembling a collection of compounds that, when combined with WIN Site inhibitor, synergistically inhibit growth of MLL-rearranged leukemia cells.
2023-07-04 | PXD035129 | Pride
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: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:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. We report genome-wide 5hmC enrichment profiles and RNA-Seq gene expression in MLL-AF9 transformed and control mouse bone marrow mononuclear cells. These 5hmC profiles are derived from selctive chemical labeling and enrichment of 5hmC containing genomic DNA fragments, while the RNA-Seq expression profiles are generated from polyA enriched RNA
2015-12-14 | E-GEOD-42990 | biostudies-arrayexpress
Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option. Experiment Overall Design: RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).
2009-01-26 | E-GEOD-13714 | biostudies-arrayexpress
Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year of age) is characterized by a high incidence of MLL translocations which is associated with a poor prognosis. Contributing to this poor prognosis is cellular drug resistance, especially to glucocorticoids like prednisolone. Although in vitro prednisolone resistance mechanisms have been proposed in pediatric ALL, it has never been studied in MLL-rearranged infant ALL, which are highly resistant to glucocorticoids in vitro and in vivo. We analyzed primary MLL-rearranged infant ALL expression profiles, which were either in vitro prednisolone-resistant or prednisolone-sensitive, in order to study in vitro prednisolone resistance.
2011-10-12 | E-GEOD-32962 | biostudies-arrayexpress
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
2015-12-14 | GSE42990 | GEO
Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option.
2009-01-01 | GSE13714 | GEO