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Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP)

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE81300 | GEO | 2016/06/02

SECONDARY ACCESSION(S): PRJNA321208

REPOSITORIES: GEO

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Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP)

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-06-02 | E-GEOD-81300 | biostudies-arrayexpress

Identification of Kdm4a and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP) [ChIP-seq]

Project description:In this study we identify genes, that are bound by Kdm4a and Kdm4c in L-GMP cells.

2016-06-02 | GSE81299 | GEO

Identification of Kdm4a and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP) [ChIP-seq]

Project description:In this study we identify genes, that are bound by Kdm4a and Kdm4c in L-GMP cells. MLL-AF9 transformed L-GMP cell lines conditional knockout for Kdm4a, b and c, were derived from leukemic mice. The cells were treated with 4-hydroxytamoxifen and chromatin was prepared from untreated cells (Ctrl) and cells treated for 96hr.

2016-06-02 | E-GEOD-81299 | biostudies-arrayexpress

Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP) [gene expression]

Project description:In this study we identify genes, that are deregulated in Kdm4a, b and c triple knockout L-GMP cells compared WT L-GMP cells.

2016-06-02 | GSE81298 | GEO

Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP) [gene expression]

Project description:In this study we identify genes, that are deregulated in Kdm4a, b and c triple knockout L-GMP cells compared WT L-GMP cells. Four MLL-AF9 transformed L-GMP cell lines conditional knockout for Kdm4a, b and c, were derived from leukemic mice. The cells were treated with 4-hydroxytamoxifen and total RNA was prepared from 0h, 48h and 96h time points.

2016-06-02 | E-GEOD-81298 | biostudies-arrayexpress

Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP)

Project description:Identification of Kdm4a, b and c target genes in MLL-AF9 transformed mouse GMPs (L-GMP)

| PRJNA321208 | ENA

Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.

Project description:The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

| S-EPMC2430522 | biostudies-literature

Protocol to establish a stable <i>MLL-AF9</i>_AML mouse model.

Project description:Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies. Here, we describe a mouse MLL-AF9_AML model to investigate AML. We have optimized the protocols for retrovirus infection, bone marrow transplantation (BMT), and leukemia monitoring to create a stable mouse model. In particular, we have used two rounds of BMT to enhance stability and efficiency. This model can be used to conduct drug administration and/or other interventions easily. For complete details on the use and execution of this protocol, please refer to Zhao et al. (2022).

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MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia.

Project description:ObjectiveThe aim of this study was to better understand how mixed lineage leukemia (MLL) fusion proteins deregulate the expression of genes critical for leukemia.Materials and methodsThe transforming domain of one of the most common MLL fusion partners, AF9, was immunopurified after expression in myeloblastic M1 cells, and associating proteins were identified by mass spectrometric analysis. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction was used to determine how binding of associating proteins compare across Hoxa9 and Meis1 in cell lines with and without MLL fusion proteins and how binding is altered during gene down-regulation and differentiation.ResultsConsistent with earlier purifications of ENL and AF4 from 293 cells, the 90 amino acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10. This complex, termed elongation assisting proteins (EAPs), also contains the RNA polymerase II C-terminal domain kinase Cdk9/Cyclin T1/T2 (pTEFb) and the histone H3 lysine 79 methyltransferase Dot1L. Myeloid cells transformed by MLL fusions show higher levels and a broader distribution of EAP components at genes critical for leukemia. Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.ConclusionsThe findings suggest that MLL fusion proteins deregulate genes critical for leukemia by excessive recruitment and impaired dissociation of EAP from target loci.

| S-EPMC3038424 | biostudies-literature

CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis.

Project description:Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.

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