Gene expression profiles upon Meis1 knockout in Hoxa9/Meis1-induced AML
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50645 | GEO | 2015/01/01
SECONDARY ACCESSION(S): PRJNA218195
REPOSITORIES: GEO
Similar Datasets
Project description:Meis1 is found cooperatively activated with Hoxa7/a9 in AML, and it indeed promotes leukemogenic activities of Hoxa9. It is important to identify downstream target genes of Meis1 to understand its cooperative activity with Hoxa9 in leukemogenesis. We used microarrays to detail the global programme of gene expression upon Meis1 knockout. Murine primary bone marrow cells of the Rosa26-Cre-ERT2 knock-in mouse were transformed by retroviral transduction of Hoxa9 and floxed Meis1. The immortalized bone marrow cells were treated with 2 μM of 4-hydroxytamoxifen to delete Meis1 cDNA. Gene expression profiles were compared between the original Hoxa9/Meis1-expressing cells and Meis1 deleted (Hoxa9 only) cells.
2015-01-01 | E-GEOD-50645 | biostudies-arrayexpress
Project description:The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feed-forward loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, we show that Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
2017-06-14 | PXD004192 | Pride
Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and miRNA expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. miRNA expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple miRNA including a set not previously implicated as Meis1 targets.
2017-04-27 | GSE74566 | GEO
Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and gene expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. Gene expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple genes including a set not previously implicated as Meis1 targets.
2016-09-01 | GSE75272 | GEO
Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and gene expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. Gene expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple genes including a set not previously implicated as Meis1 targets. Murine bone marrow cells transduced with Hoxa9-GFP + empty MIY vector were compared to Hoxa9+Meis1 cells or Hoxa9+Meis1 with deleted homeodomain (DHD) cells and cultured for three or four weeks before harvest for miRNA expression array. Four independent experiments were performed for each of the three different conditions included in the study. Cells from all samples were also transplanted into lethally irradiated mice to test for their transforming and leukemic potential.
2016-09-01 | E-GEOD-75272 | biostudies-arrayexpress
Project description:Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation.
2018-09-05 | GSE103447 | GEO
Project description:Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation.
2018-09-05 | GSE103448 | GEO
Project description:Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer-specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/ and the histone H3K4 methyltransferase MLL3/MLL4 complex. The HOXA9 function at de novo enhancers is distinct from its physiological role at enhancers during normal hematopoietic development. The MLL3/MLL4 complex physically interacts with HOXA9 and is required both for the active enhancer signatures at de novo enhancers and HOXA9/MEIS1-mediated leukemogenesis. The findings suggest that therapeutic targeting of HOXA9-dependent histone methylation could be an effective therapeutic strategy in acute leukemia associated with HOXA9 over expression.
2018-09-05 | GSE103446 | GEO
Project description:Identification of the genome-wide binding sites of Hoxa9 and C/EBPα in a murine myeloblastic cell line transformed by Hoxa9/Meis1. Over 50% of Hoxa9 binding sites are co-bound by C/EBPα, providing mechanistic insight into the requirement of C/EBPα for Hoxa9-mediated leukemogenesis. Additionally, genome-wide occupancy of H3K4 monomethylation and H3K27 trimethylation provide additional information on the functionality of Hoxa9/C/EBPα cobound loci.
2014-06-11 | GSE58361 | GEO
Project description:Identification of the genome-wide binding sites of Hoxa9 and C/EBPα in a murine myeloblastic cell line transformed by Hoxa9/Meis1. Over 50% of Hoxa9 binding sites are co-bound by C/EBPα, providing mechanistic insight into the requirement of C/EBPα for Hoxa9-mediated leukemogenesis. Additionally, genome-wide occupancy of H3K4 monomethylation and H3K27 trimethylation provide additional information on the functionality of Hoxa9/C/EBPα cobound loci. Examination of two transcription factor binding sites and two histone modifications in a transformed cell line.
2014-06-11 | E-GEOD-58361 | biostudies-arrayexpress