Non-toxic direct targeted therapy for MLL-fusion driven leukemias
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ABSTRACT:
PROVIDER: PRJNA839020 | ENA |
REPOSITORIES: ENA
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Project description:Improving the poor prognosis of infant leukemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven pediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, Disulfiram, based on its efficient ablation of MLL fusion proteins. The consequences of drug-induced MLL-fusion inhibition was confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and CHIP-qPCR and CHIP-seq analysis. All statistical tests were two-sided. Drug-induced inhibition of MLL-fusion proteins by Disulfiram resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukemia progression in vivo. Mechanistically, Disulfiram abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukemic programs setup by the MLL-fusion protein. Disulfiram can directly inhibit MLL-fusion proteins and demonstrates antitumor activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly target the initiating oncogenic MLL-fusion protein.
2022-08-01 | GSE203203 | GEO
Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.
2018-05-25 | PXD009338 | Pride
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. This SuperSeries is composed of the SubSeries listed below.
2008-11-04 | GSE12363 | 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
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:Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene result in fusion proteins which retain the N-terminal portion of MLL fused with one of more than 70 different fusion partners. The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL fusion proteins in a fusion partner independent manner. We have demonstrated that blocking the menin-MLL interaction using small molecule inhibitor inhibits oncogenic activity of different MLL fusion proteins according to a mechanism that is independent on the fusion partner.
2018-06-09 | GSE69740 | GEO
Project description:We report the genome wide distribution of H3K79 dimethylation in mouse MLL-AF6 positive leukemias to assess whether this epigenetic mark drives MLL-target gene expression. Examination of H3K79 dimethylation in bone marrow cells from sacrificed terminally ill MLL-AF6 positive leukemic mice. The retroviral MSCV-IRES-neo-MLL-AF6 construct was transduced into mouse bone marrow lineage negative Kit +, Sca + (LSK) cells and these cells were injected after G418 selection into irradiated syngenic mice to establish MLL-AF6 positive leukemias.
2013-04-03 | E-GEOD-43062 | biostudies-arrayexpress
Project description:We report the genome wide distribution of H3K79 dimethylation in mouse MLL-AF6 positive leukemias to assess whether this epigenetic mark drives MLL-target gene expression.
2013-04-03 | GSE43062 | GEO
Project description:The Mixed Lineage Leukemia 1 protein (MLL1) is an important epigenetic regulator required for the maintenance of gene activation during development. MLL1 chromosome translocations produce novel fusion proteins that cause aggressive leukemias in humans. Individual MLL1 fusion proteins have distinct leukemic phenotypes even when expressed in the same cell type, but how this distinction is delineated on a molecular level is poorly understood. Here we highlight a unique molecular mechanism whereby MLL-AF4 specifically activates the RUNX1 gene and the RUNX1 protein interacts with the product of the reciprocal AF4-MLL translocation. These results support a mechanism of leukemic growth whereby two oncogenic fusion proteins cooperate by activating a target gene and then interacting directly with its downstream product ChIP-seq using RUNX1 antibody in SEM cells
2013-01-31 | E-GEOD-42075 | biostudies-arrayexpress
Project description:Background: MLL (KMT2A)-EB1 (MAPRE1) fusion was identified in a patient with de novo pro-B acute lymphoblastic leukemia. To investigate the leukemogenesis of MLL-EB1 fusion, a retroviral transduction of MLL-EB1 to murine bone marrow cells was performed. A frequent MLL fusion, MLL-AF10(OM-LZ), was used as a positive control. Results: Two MLL-EB1 immortalized cell lines (ME1 and ME2G), and a MLL-AF10(OM-LZ) immortalized cell line (12G) were generated. Microarray results showed that many genes including Evi1 and Ets1 were differentially expressed in ME1/ME2G and 12G cell lines.
2017-06-02 | GSE82156 | GEO