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Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb

ABSTRACT: Using an integrative approach combining a Tet-off conditional AML mouse model, global expression profiling following suppression of the driving MLL-AF9 oncogene, and a new Tet-on conditional shRNA expression system we have identified Myb as critical mediator of addiction to MLL-AF9. Suppression of Myb in established AML in vivo terminates aberrant self-renewal and triggers a terminal myeloid differentiation program that precisely phenocopies the effects of suppressing MLL-AF9. Remarkably, suppressing Myb effectively eradicates aggressive and chemotherapy resistant AML. To further investigate Myb dependent transcriptional programs involved in mediating aberrant self-renewal in leukemia, we globally surveyed gene expression changes following acute shRNA-induced suppression of Myb in an established Tet-on competent model of MLL-AF9;NrasG12D-induced AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE30745 | GEO | 2011/08/05

SECONDARY ACCESSION(S): PRJNA154721

REPOSITORIES: GEO

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Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb

Project description:Using an integrative approach combining a Tet-off conditional AML mouse model, global expression profiling following suppression of the driving MLL-AF9 oncogene, and a new Tet-on conditional shRNA expression system we have identified Myb as critical mediator of addiction to MLL-AF9. Suppression of Myb in established AML in vivo terminates aberrant self-renewal and triggers a terminal myeloid differentiation program that precisely phenocopies the effects of suppressing MLL-AF9. Remarkably, suppressing Myb effectively eradicates aggressive and chemotherapy resistant AML. To further investigate Myb dependent transcriptional programs involved in mediating aberrant self-renewal in leukemia, we globally surveyed gene expression changes following acute shRNA-induced suppression of Myb in an established Tet-on competent model of MLL-AF9;NrasG12D-induced AML. To enable regulatable suppression of Myb in AML, we retrovirally transduced established Tet-on competent MLL-AF9;NrasG12D induced AML cells with TRMPV-Neo vectors (Zuber et al., Nature Biotech, 2010) harboring shRNAs targeting Myb (shMyb.2572 and shMyb.2652), a control shRNA targeting Renilla Luciferase (shRen.713), or an empty miR30 cassette of the recipient cloning vector (Rec). Following drug selection, shRNA expression was induced by doxycycline treatment and total RNA was isolated from sorted shRNA expressing (Venus+/dsRed+) leukemia cells after 3 days of dox treatment, and subjected to Affymetrix microarray expression analysis. Expression profiles following expression of two independent Myb shRNAs were compared to those observed after induction in shRen.713- and Rec-expressing control samples (each in 3 biological replicates).

2011-08-04 | E-GEOD-30745 | biostudies-arrayexpress

AML mouse models

Project description:This SuperSeries is composed of the following subset Series: GSE30745: Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb GSE30746: Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9 Refer to individual Series

2011-08-04 | E-GEOD-30747 | biostudies-arrayexpress

RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by tet-regulated MLL-AF9 co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in Tet-Off MLL-AF9 AML cells in vitro partially phenocopies MLL-AF9 depletion and results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. To compare gene expression changes associated with enforced Id2 expression and MLL-AF9 withdrawal, RNA sequencing analysis was performed on Tet-off MLL-AF9 cells transduced with an Id2 over-expressing or a control vector, or upon MLL-AF9 dox-inducible knock-down. Primary AMLs driven by Tet-off inducible MLL/AF9 expression linked to dsRED reporter, in association with oncogenic NRASG12D (Tet-off MLL-AF9) were generated by reconstituting lethally irradiated congenic mice with foetal liver cells co-transduced with a Tet-Off-MLL-AF9-dRED retroviral vector and a second vector co-expressing NRASG12D together with the Tet-Off responsive transcriptional activator. RNA sequencing analysis sequencing analysis was performed on Tet-Off MLL-AF9/dsRED+ AML cells treated in vitro with doxycycline (DOX) for 4 days to inactivate MLL-AF9 expression or left untreated (UT). For the Id2 over-expression experiment, Tet-Off MLL-AF9/dsRED+ AML cells were transduced in vitro with an Id2-GFP or a control-GFP retroviral vector. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis.

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RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

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Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9

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2011-08-04 | E-GEOD-30746 | biostudies-arrayexpress

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen).

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