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Role of LEDGF/p75 in MLL chemoresistance

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164751 | GEO | 2021/01/14

REPOSITORIES: GEO

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Role of HRP2 in mixed lineage leukemia compared to its paralog LEDGF/p75

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

LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis

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

Role of LEDGF/p75 in MLL chemoresistance

Project description:Role of LEDGF/p75 in MLL chemoresistance

| PRJNA691895 | ENA

LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis

Project description:LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis

| PRJNA411792 | 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

ASH1L links histone H3 lysine 36 di-methylation to leukemia

Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.

2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress

ASH1L links histone H3 lysine 36 di-methylation to leukemia

2016-07-01 | GSE73528 | GEO

Identification of LEDGF-regulated genes.

Project description:The LEDGF transcript from the PSIP1 gene was knocked down using RNAi technology. The resulting 293T derived cell line (293TsiLL) was compared to a control cell line (293TsiScram) using microarray analysis. Genes identified as being modulated by LEDGF were preferential targets of HIV integration. Keywords: gene knockdown effects

2005-11-07 | GSE3485 | GEO

MAT2A as key regulator and therapeutic target in MLL leukemogenesis

Project description:Epigenetic dysregulation plays a pivotal role in MLL pathogenesis, therefore serving as suitable therapeutic point of attack. SAM is the universal methyl donor in human cells and is synthesized by MAT2A. MAT2A is already known to be deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLLr leukemia model, faithfully mimicking MLL patients’ pathology with indefinite growth potential in in vitro culture, to evaluate the unknown role of MAT2A as therapeutic target. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr specific enhanced response to PF-9366, a new MAT2A inhibitor, by alteration of proliferation, viability, differentiation, apoptosis and cell cycling. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases DOT1L and PRMT5, revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.

2020-06-22 | GSE141839 | GEO

Three-dimensional chromatin landscapes in MLLr AML [Micro-C]

Project description:Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with both pediatric and adult leukemia. However, the treatment options for these aggressive MLLr leukemias are limited due to the genomic complexity and dynamics of 3D structure in oncogene transcription and leukemia development. Here, we use Micro-C and transcriptome profiling to examine the MLLr-driven aberrant 3D genome architecture in gene-edited MLL-AF9 AML samples with biologically matched healthy donors. Recurrent and MLLr-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing in the same AML samples also revealed extensive and recurrent MLLr-specific promoter–enhancer and promoter–silencer loops. Overall, this study highlights the critical regulatory elements and provides rational and effective targeting strategy in MLLr AML.

2024-02-20 | GSE244471 | GEO

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