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Cell of origin in AML: Susceptibility to MN1-induced transformation is regulated by the MEIS1/abdB-like HOX protein complex

ABSTRACT: The molecular mechanism defining susceptibility of normal cells to oncogenic transformation may be a valuable therapeutic target. We characterized the cell of origin and its critical pathways in MN1 leukemias. Common myeloid (CMP), but not granulocyte-macrophage progenitors (CMP) could be transformed by constitutively overexpressed MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that leukemogenicity of MN1 required the MEIS1/abdB-like HOX protein complex. Colocalization studies by ChIP-seq identified common chromatin targets of MN1 and MEIS1 that were associated with open chromatin and transcriptional activation. Transcriptional repression of MEIS1 target sites in established MN1 leukemias had antileukemic activity. As MN1 relies on but can not activate expression of MEIS1/abdB-like HOX proteins, transcriptional activity of these genes determines which cell is the cell of origin in MN1 leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE22923 | GEO | 2011/05/19

SECONDARY ACCESSION(S): PRJNA127611

REPOSITORIES: GEO

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Cell of origin in AML: Susceptibility to MN1-induced transformation is regulated by the MEIS1/abdB-like HOX protein complex

Project description:The molecular mechanism defining susceptibility of normal cells to oncogenic transformation may be a valuable therapeutic target. We characterized the cell of origin and its critical pathways in MN1 leukemias. Common myeloid (CMP), but not granulocyte-macrophage progenitors (CMP) could be transformed by constitutively overexpressed MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that leukemogenicity of MN1 required the MEIS1/abdB-like HOX protein complex. Colocalization studies by ChIP-seq identified common chromatin targets of MN1 and MEIS1 that were associated with open chromatin and transcriptional activation. Transcriptional repression of MEIS1 target sites in established MN1 leukemias had antileukemic activity. As MN1 relies on but can not activate expression of MEIS1/abdB-like HOX proteins, transcriptional activity of these genes determines which cell is the cell of origin in MN1 leukemia. We have showed at the single cell level that CMPs, but not GMPs, are susceptible to MN1-induced transformation. To identify transcriptional differences between CMPs and GMPs that may explain this difference in susceptibilities to MN1 transformation we produced gene expression profiles (two biological replicates in each experimental arm) of bone marrow cells from MN1 leukemic mice and mature myeloid bone marrow cells (Gr1+/CD11b+) from healthy mice and compared those to already published gene expression profiles of CMPs and GMPs (Krivtsov, A.V., et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818-822).

2011-05-19 | E-GEOD-22923 | biostudies-arrayexpress

Gene expression profiles in mouse common myeloid progenitor (CMP) and leukemia cells expressing full-length MN1 or truncated versions of MN1 protein

2013-06-13 | GSE38767 | GEO

Gene expression profiles in mouse common myeloid progenitor (CMP) and leukemia cells expressing full-length MN1 or truncated versions of MN1 protein

Project description:We used Affymetrix microarrays to characterize gene expression profiles that were perturbed in common myeloid progenitor (CMP) cells due to enforced expression of full-length or truncated forms of MN1. Expression profiles of MN1-induced leukemias arising from whole bone marrow transduction were also compared with the profiles obtained from the CMP cells. Lineage negative mouse bone marrow cells were transduced with retroviral vectors expressing full-length or truncated MN1 proteins. After 2 days in culture, cells were FACS-sorted for GFP expression and cultured for a further 3 days in growth media. After 5 days total, RNA was isolated and processed for microarray analysis. RNA was also prepared for microarray analysis from leukemias arising in mice following whole bone marrow transduction with full-lenght MN1.

2013-06-13 | E-GEOD-38767 | biostudies-arrayexpress

Epigenomic profiling studies of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided R882H-mutated DNMT3A, H3K4me1, H3K4me3 and H3K27me3 ChIP-seq profiling data of RH-RAS LSCs, and H3K4me1 ChIP-seq data in HOXA9-MEIS1 LSCs.

2016-06-23 | GSE71474 | GEO

MEIS1-HLF axis regulates oxidative metabolism and is essential for MLL-fusion gene leukemia

Project description:The pathogenesis of MLL-fusion gene leukemias has been linked to upregulated expression of HOX genes and of the HOX-cofactor Meis1.The functions of the HOX/MEIS1 complex in leukemia however remain unclear. Here, we used inducible MEIS1-knockout mice coupled with MLL-AF9 knockin mice to decipher the role of MEIS1 in leukemia. We found that MEIS1 was critically required for established leukemia. Further, MEIS1 loss led to increased oxygen flux and apoptosis, while hypoxia reversed these effects. Finally, we identify HLF as a downstream mediator of MEIS1 in leukemia. Overexpression of HLF prevents oxygen flux and rescues the leukemia phenotype in MEIS1-deficient cells. Thus, the oncogenic effects of MEIS1 are at least partly mediated by an HLF-driven hypoxic state.

2015-05-21 | GSE58732 | GEO

Epigenomic profiling studies of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided R882H-mutated DNMT3A, H3K4me1, H3K4me3 and H3K27me3 ChIP-seq profiling data of RH-RAS LSCs, and H3K4me1 ChIP-seq data in HOXA9-MEIS1 LSCs. Genome-wide binding of R882H-mutated DNMT3A (Myc tagged; ChIP-seq with 9e10 anti-Myc antibodies) and histone modification profiles for H3K4me1, H3K4me3 and H3K27me3 were generated by ChIP-seq using specific antibodies in RH-RAS LSCs. Genome-wide H3K4me1 histone modification profiles were generated by ChIP-seq using H3K4me1 specific antibody in HOXA9-MEIS1 LSCs.

2016-06-23 | E-GEOD-71474 | biostudies-arrayexpress

Gene expression changes induced by overexpression of MN1 and MN1VP16 in murine bone marrow cells

Project description:Myeloid differentiation is blocked in acute myeloid leukemia (AML), but the molecular mechanisms are not well characterized. MN1 is overexpressed in some AML patients and confers resistance to all-trans retinoic acid (ATRA)-induced differentiation. To understand the role of MN1 as a transcriptional regulator in myeloid differentiation, we fused transcriptional activation (VP16) or repression (M33) domains with MN1 and characterized these cells in vivo. Transcriptional activation of MN1 target genes induced myeloproliferative disease with long latency and differentiation potential to mature neutrophils. A large proportion of differentially expressed genes between leukemic MN1 and differentiation-permissive MN1VP16 cells belonged to the immune response pathway like Irf8 and Ccl9. As MN1 is a co-factor of MEIS1 and RARA, we compared chromatin occupancy between MN1, MEIS1 and RARA. Immune response genes that were upregulated in MN1VP16 cells were co-targeted by MN1 and MEIS1, but not RARA, suggesting that myeloid differentiation is blocked through transcriptional repression of shared target genes of MN1 and MEIS1. Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of MN1-induced leukemia. Our data show that MN1 prevents activation of the immune response pathway, and suggest that restoration of Irf8 signalling as a novel therapeutic target in AML.

2015-01-01 | GSE48819 | GEO

Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided enhanced Reduced Representation Bisulfite Sequencing (eRRBS) DNA methylome profiling data showing effect of DNMT3A R882H mutation or WT expression on hematopoietic stem/progenitor cells with NRAS G12D co-transduction.

2016-06-23 | GSE71473 | GEO

Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction.

2016-06-23 | GSE71472 | GEO

Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction.

2016-06-23 | GSE71437 | GEO

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