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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Sox4 is a key oncogenic target in C/EBP? mutant Acute Myeloid Leukemia

ABSTRACT: Mutation or epigenetic silencing of the transcription factor C/EBP? is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBP? whereby its expression is inversely correlated with C/EBP? activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBP? AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBP? inactivation contributes to the development of leukemias with a distinct LIC phenotype. K/L (bi-allelic Cebpa mutations) leukemic mice and Sox4 overexprssing leukemic mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the C57/BL6 wild type mice.

ORGANISM(S): Mus musculus

SUBMITTER: Henry Yang

PROVIDER: E-GEOD-45430 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia

Project description:Mutation or epigenetic silencing of the transcription factor C/EBPa is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPa whereby its expression is inversely correlated with C/EBPa activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPa AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPa inactivation contributes to the development of leukemias with a distinct LIC phenotype. A ChIP-seq sample of C/EBPa in Macrophages is used in this study

2014-01-08 | E-GEOD-50565 | biostudies-arrayexpress

Sox4 is a key oncogenic target in C/EBPα mutant Acute Myeloid Leukemia

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Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

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