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The quantitative analysis of transcriptomes derived from MLL-AF10 flox cells and MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells with or without the treatment of 4-OHT

ABSTRACT: Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region in frame to partner genes , and the resultant fusion proteins can cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as the HoxA cluster and Meis1, but the underlying mechanisms remain elusive. We found that the MLL-AF10 fusion recruits Tip60 to the Hoxa9 locus, where it acetylates H2A.Z, thereby promoting Hoxa9 expression. Following conditional deletion of Tip60, hypoacetylation of H2A.Z was accompanied by recruitment of Ezh2, the catalytic subunit of PRC2, suggesting that nucleosomes with hypoacetylated H2A.Z are the preferential targets of Ezh2. Our findings suggest that MLL-AF10 achieves active chromatin states by recruiting Tip60, which acetylates H2A.Z to prevent gene silencing by Ezh2.

ORGANISM(S): Mus musculus

PROVIDER: GSE142558 | GEO | 2021/06/30

REPOSITORIES: GEO

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The genome-wide maps of H3K27me3 in MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells (MATIP cells) with or without the treatment of 4-OHT

Project description:Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region in frame to partner genes , and the resultant fusion proteins can cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as the HoxA cluster and Meis1, but the underlying mechanisms remain elusive. We found that the MLL-AF10 fusion recruits Tip60 to the Hoxa9 locus, where it acetylates H2A.Z, thereby promoting Hoxa9 expression. Following conditional deletion of Tip60, hypoacetylation of H2A.Z was accompanied by recruitment of Ezh2, the catalytic subunit of PRC2, suggesting that nucleosomes with hypoacetylated H2A.Z are the preferential targets of Ezh2. Our findings suggest that MLL-AF10 achieves active chromatin states by recruiting Tip60, which acetylates H2A.Z to prevent gene silencing by Ezh2.

2021-06-30 | GSE142557 | GEO

Assesment of gene expression upon AF10 deletion in MLL-AF9 secondary leukemia

Project description:Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Primary MLL-AF9 leukemias in the AF10 floxed background (homozygous) were transduced with MSCV-IRES-tdTomato (MIT) or the Cre recombinase expressing MIT vector, cells were sorted and injected into secondary recipient mice to generate Af10 floxed (MIT) or deleted (CRE) leukemias. BM cells fresly harvested from these leukemias were sorted for tdTomato expression and used for microarrays. BM cells from Hoxa9-Meis1 transduced primary leukemias were used for comparison.

2014-09-08 | E-GEOD-54499 | biostudies-arrayexpress

The quantitative analysis of transcriptomes derived from MLL-AF10 flox cells and MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells with or without the treatment of 4-OHT

Project description:The quantitative analysis of transcriptomes derived from MLL-AF10 flox cells and MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells with or without the treatment of 4-OHT

| PRJNA597557 | ENA

Transcription profiling of human MLL-AF10 myeloid leukemia cellular subsets

Project description:Leukemia cells from mice with MLL-AF10 AML were fractionated into separate sub-populations on the basis of c-kit expression, which correlates with MLL LSC frequency (Somervaille and Cleary, 2006). The sorted AML sub-populations exhibited substantial differences in their frequencies of AML CFCs/LSCs (mean 14-fold) and morphologic features, consistent with a leukemia cell hierarchy with maturation through to terminally differentiated neutrophils. Experiment Overall Design: Leukemic splenocytes from four mice with MLL-AF10 AML were sub-fractionated in to c-kit high and c-kit negative sub-populations by FACS.

2009-02-21 | E-GEOD-13692 | biostudies-arrayexpress

Expression profiling of MLL-AF10 myeloid leukemia cellular subsets

2009-02-06 | GSE13692 | GEO

Expression data from mouse MLL/AF10(OM-LZ) myeloid leukemia cells harboring wild-type KRAS, KRAS-G12C, wild-type PTPN11, PTPN11-G503A, without or with Hoxa11

Project description:Cooperation of MLL/AF10 with RAS pathway mutations accelerated myeloid leukemia development. The detail molecular mechanism is analyzed by identification of the differentially expressed genes between MLL/AF10 cells harboring wild-type and mutant RAS pathway genes and by with or without Hoxa11. We used cDNA microarray to compare transcriptomes between mouse MLL/AF10 myeloid leukemia cells harboring wild-type KRAS and harboring KRAS-G12C (AKw1G and AK3G), or between MLL/AF10 cells harboring wild-type PTPN11 and harboring PTPN11-G503A (APw-1 and APm-1), or between MLL/AF10 cells without and with Hoxa11 (12G-V and 12G-H11).

2020-07-01 | GSE134586 | GEO

Microarray data of mouse MLL-AF10 leukemia cells with or without IKK inhibitor treatment

Project description:MLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations, however the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-kB signaling in MLL leukemia. Suppression of NF-kB led to robust anti-leukemia effects that phenocopied loss of functional MLL oncoprotein or associated epigenetic cofactors. The NF-kB subunit RELA occupies promoter regions of crucial MLL target genes and sustains the MLL-dependent leukemia stem cell program. IKK/NF-kB signaling is required for wild-type MLL and fusion protein retention and maintenance of associated histone modifications providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLL leukemias. MLL-AF10 cells were treated with 0.5ÂµM IKK inhibitor or vehicle. Each group contains triplicate samples.

2013-09-19 | E-GEOD-46250 | biostudies-arrayexpress

Assesment of gene expression upon AF10 deletion in MLL-AF9 secondary leukemia

2014-09-08 | GSE54499 | GEO

MLL-EB1 fusion immortalized murine bone marrow cells

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

shRNA profiling of human MLL cells reveals HOXA9 is required for survival in human MLL rearranged acute leukemias

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

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