LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis
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ABSTRACT:
PROVIDER: PRJNA411792 | ENA |
REPOSITORIES: ENA
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Project description:Mixed-lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the MLL gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with Lens Epithelium-Derived Growth Factor (LEDGF/p75; encoded by the Psip1 gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL fusion-mediated transformation and for the expression of downstream MLL-regulated genes like HOXA9 and MEIS1. In light of the development of a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional Psip1 knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. Psip1 knockout mice were viable but showed several defects in hematopoiesis, reduced colony-forming activity in vitro, decreased expression of Hox genes in hematopoietic stem cells and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/p75 is dispensable for steady state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of MLL-rearranged leukemia.
2017-09-30 | GSE104138 | GEO
Project description:The study has been focused on the characterization of the role of LEDGF/p75 in chemiresistance in pediatric leukemia Abstract: MLL is an aggressive subtype of leukemia with a poor prognosis that mostly affects pediatric patients. MLL-rearranged fusion proteins (MLLr) induce aberrant target gene expression resulting in leukemogenesis. MLL and its fusions are tethered to chromatin by LEDGF/p75, a transcriptional co-activator that specifically recognizes H3K36me2/3. LEDGF/p75 is ubiquitously expressed and associated with regulation of gene expression, autoimmune responses and HIV replication. LEDGF/p75 was proven to be essential for leukemogenesis in MLL. Apart from MLL, LEDGF/p75 has been linked to lung, breast and prostate cancer. Intriguingly, LEDGF/p75 interacts with Med-1, which co-localizes with BRD4. Both are known as co-activators of super-enhancers. Here, we describe LEDGF/p75-dependent chemoresistance of MLLr cell lines. Investigation of the underlying mechanism revealed a role of LEDGF/p75 in the cell cycle and in survival pathways and showed that LEDGF/p75 protects against apoptosis during chemotherapy. Remarkably, LEDGF/p75 levels also affected expression of BRD4 and Med1. Altogether, our data suggest a role of LEDGF/p75 in cancer survival, stem cell renewal, and activation of nuclear super enhancers.
2021-01-14 | GSE164751 | GEO
Project description: Not available
| S-EPMC5755044 | biostudies-literature
Project description:Mixed lineage leukemia-rearranged (MLLr) leukemia is a genetically distinct subtype of leukemia driven by a reciprocal chromosomal translocation or partial tandem duplications of internal coding regions of the MLL gene KMT2A. These rearrangements result in in-frame genes, translated to oncogenic fusion proteins deregulating the MLL target genes (e.g. HoxA family, Meis1, Cdk6), promoting leukemogenesis and tumor progression. To regulate gene expression, unstructured N-terminal motifs found in MLL form a ternary complex with menin and the integrase binding domain (IBD) of the p75 splice variant of Lens Epithelium Derived Growth Factor (LEDGF/p75). Formation of the ternary complex is crucial for MLL-r leukemogenesis. Hepatoma derived growth factor related protein 2 (HRP2) is the only human paralog of LEDGF/p75 with identical functional domains. We investigated its role in normal hematopoiesis and leukemia. We demonstrate that adult Hrp2 knockout mice can be distinguished from their wild type littermates by increased neutrophils in the hematopoietic system. Colony formation experiments and Gene Set Enrichment Analysis on lin- HSC hinted towards a stem-like state supported by HRP2. In context of leukemia, we observe a more general role for HRP2 in the survival of leukemic cells independently of MLL.
2020-07-11 | GSE154202 | GEO
Project description:Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here we show that the SET domain and thus HMT activity of MLL1 is dispensable for maintaining HSCs and for supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation was selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 was sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function. 11 Samples, 5 controls and 5 KOs with antibodies H3K4me1, H3K4me3, and H3K27Ac. One input Sample.
2014-04-03 | E-GEOD-56456 | biostudies-arrayexpress
Project description:Role of LEDGF/p75 in MLL chemoresistance
| PRJNA691895 | ENA
Project description:Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here we show that the SET domain and thus HMT activity of MLL1 is dispensable for maintaining HSCs and for supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation was selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 was sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function.
2014-04-03 | GSE56456 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE16432: MSI2 regulates hematopoiesis and accelerates leukemogenesis GSE22773: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible) GSE22774: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK) GSE22775: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines) Refer to individual Series
2010-07-21 | E-GEOD-22778 | biostudies-arrayexpress
Project description:Comparative gene expression profiling of olfactory enshealting cells : p75 High vs p75 Low cells population
2011-07-20 | GSE30797 | GEO
Project description:Comparative gene expression profiling of olfactory enshealting cells : p75 High vs p75 Low cells population Two-color experiment, p75 high(Cy5)/p75Low (Cy3). Biological replicates: 4 . Paired samples.
2011-07-19 | E-GEOD-30797 | biostudies-arrayexpress