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Frequent derepression of the mesenchymal transcription factor gene in acute myeloid leukemia (mouse)

ABSTRACT: Murine CD45.1+ CD117+ BM cells were co-transduced pairwise with retroviral vectors expressing Hoxa9, Meis1, Foxc1 or a control empty vector. Ninety-six hours later 10^6 drug resistant cells were transplanted into CD45.2+ irradiated congenic recipients. To investigate the consequences of FOXC1 expression on the transcriptome in murine AML, we performed exon array analysis using flow sorted CD117+Gr1+ leukemia cells recovered from sick mice (Hoxa9/control; Moxa9/Meis1; or Hoxa9/FOXC1 leukemias; 3 mice per cohort).

ORGANISM(S): Mus musculus

PROVIDER: GSE66253 | GEO | 2015/09/17

SECONDARY ACCESSION(S): PRJNA276270

REPOSITORIES: GEO

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Frequent derepression of the mesenchymal transcription factor gene in acute myeloid leukemia (mouse)

Project description:Murine CD45.1+ CD117+ BM cells were co-transduced pairwise with retroviral vectors expressing Hoxa9, Meis1, Foxc1 or a control empty vector. Ninety-six hours later 10^6 drug resistant cells were transplanted into CD45.2+ irradiated congenic recipients. To investigate the consequences of FOXC1 expression on the transcriptome in murine AML, we performed exon array analysis using flow sorted CD117+Gr1+ leukemia cells recovered from sick mice (Hoxa9/control; Moxa9/Meis1; or Hoxa9/FOXC1 leukemias; 3 mice per cohort). Nine exon arrays total; 3 arrays for each cohort (Hoxa9/control; Moxa9/Meis1; or Hoxa9/FOXC1), each from a separate mouse.

2015-09-17 | E-GEOD-66253 | biostudies-arrayexpress

PBX3 cooperates with MEISI in causing rapid acute myeloid leukemia and recapitulates the core transcriptome of MLL-rearranged leukemia

Project description:To investigate whether co-expression of PBX3/MEIS1 can mimic that of MLL-AF9, HOXA9/MEIS1 or HOXA9/PBX3 in inducing leukemogenesis, we conducted in vivo mouse bone marrow transplantation (BMT) assays. Briefly, normal mouse bone marrow (BM) progenitor (i.e., lineage negative; Lin-) cells collected from B6.SJL (CD45.1) donor mice (CD45.1) were retrovirally co-transduced with MSCVneo-MLL-AF9+MSCV-PIG (MLL-AF9), MSCVneo-HOXA9+MSCV-PIG (HOXA9), MSCVneo-HOXA9+MSCV-PIG-MEIS1 (HOXA9+MEIS1), MSCVneo-HOXA9+MSCV-PIG-PBX3 (HOXA9+PBX3), MSCV-PIG-PBX3+MSCVneo-MEIS1 (PBX3+MEIS1), MSCVneo+MSCV-PIG-PBX3 (PBX3) , MSCVneo+MSCV-PIG-MEIS1 (MEIS1), or MSCVneo+MSCV-PIG (normal control; NC). Retrovirally transduced cells then were cultured with cytokines as well as puromycin and G418. Seven days later, the donor cells were transplanted into lethally irradiated (960 rads) 8- to 10-week-old C57BL/6 (CD45.2) recipient mice. The transplanted mice were watched for leukemogenesis. Then, gene expression profiling was conducted with bone marrow samples collected from leukemia groups and control group.

2016-03-03 | GSE68643 | GEO

Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions (3)

Project description:Here we report transcriptional and TCR specificities associated with murine open repertoire CD45.1+ CD4+ and CD4+CD8+, and CD45.2+ CD8+ and CD8+CD4+ T cells isolated from murine B16 tumors

2022-05-20 | GSE203184 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia (mRNA)

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

Gene expression profiles upon Meis1 knockout in Hoxa9/Meis1-induced AML

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

Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia

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

Hoxa9/meis1-transgenic zebrafish develops acute myeloid leukemia-like disease with rapid onset and high-penetrance

Project description:HOXA9/MEIS1 plays a synergistic causative role and overexpresses frequently in acute myeloid leukemia (AML). Hoxa9/Meis1 transgenic murine results in rapid leukemic transformation of primary bone marrow cells. However, murine model is not suitable to perform a high-throughput phenotypic screen in vivo and identify compounds for AML therapy. A transgenic zebrafish overexpresses hoxa9/meis1 need to generate. We have engineered an inducible transgenic line Tg (drl:hoxa9;hsp70:meis1) harboring hoxa9/meis1 under the draculin (drl) promoter. The downregulation of runx1, c-myb, mpx, mfap4, and gata1 in Tg (drl:hoxa9;hsp70:meis1) embryos indicated enforced hoxa9/meis1 perturbs embryonic hematopoiesis. Importantly, adult Tg (drl:hoxa9;hsp70:meis1) develops malignant myeloid disease with an abundance of myeloid precursor cells, anemia, and high mortality after a latency period (~5-months-aged) with comparable to murine model and human AML patients. Genome-wide transcription changes analysis indicated arrested differentiation genes such as gata2b, notch1b, and gfi1ab are upregulated. Leflunomide, inhibitor of enzyme dihydroorotate dehydrogenase (DHODH) which is a potential option for differentiation therapy of AML, relieves defective hematopoiesis in transgenic embryos and larvae. Collectively, we have identified an inducible malignant myeloid disease transgenic zebrafish model similar to AML and provided a unique opportunity for high-throughput in vivo chemical screening for AML therapy and study the related mechanisms.

2022-09-01 | GSE204744 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia (mRNA)

2016-09-01 | GSE75272 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia

2017-04-27 | GSE74566 | GEO

Gene expression changes upon Mll1 knockout in NUP98-HOXA9 transformed murine LSKs

Project description:We report Illumina next generation RNA sequencing (RNAseq) of NUP98-HOXA9 in vitro transformed murine LSKs upon genetic deletion of Mll1. These gene expression data illustrate that Mll1 regulates Hoxa, Hoxb and Meis1 expression in NUP98-HOXA9 transformed murine BM cells.

2016-12-11 | GSE75997 | GEO

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