Genome wide mapping of histone 3 lysine 79 dimethylation in MLL rearranged and control human leukemia cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE43063 | GEO | 2013/04/03
SECONDARY ACCESSION(S): PRJNA184353
REPOSITORIES: GEO
Similar Datasets
Project description:We report the genome wide distribution of H3K79 dimethylation in the human MLL-AF6 rearranged cell line ML2 as well as the human MOLM13 and HL60 cell lines Examination of H3K79 dimethylation in the MLL-AF6 fusion positive human leukemia cell line ML2 and control cell lines MOLM-13 and HL60. The MLL-AF6 positive ML2 cell line (obtained from DSMZ) and the cell lines HL60 and MOLM 13 were grown under standard conditions and 1 million cells were fixed/crosslinked and used for ChIP-seq with H3K79 dimethylation specific antibody Ab3594 (Abcam)
2013-04-03 | E-GEOD-43063 | 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. 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: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). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison
2008-11-04 | GSE12362 | GEO
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). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison
2008-11-04 | GSE12361 | GEO
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). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison
2008-11-04 | GSE12360 | GEO
Project description:MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program. Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells
2013-02-19 | E-GEOD-43725 | biostudies-arrayexpress
Project description:MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program.
2013-02-19 | GSE43725 | GEO
Project description:Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein-protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.
| S-EPMC8944089 | biostudies-literature
Project description:Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6 / DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
2018-04-26 | GSE95511 | GEO