Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Salam Assi

PROVIDER: E-GEOD-50565 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia.

Zhang Hong H Alberich-Jorda Meritxell M Amabile Giovanni G Yang Henry H Staber Philipp B PB Di Ruscio Annalisa A Welner Robert S RS Ebralidze Alexander A Zhang Junyan J Levantini Elena E Lefebvre Véronique V Valk Peter J M PJ Delwel Ruud R Hoogenkamp Maarten M Nerlov Claus C Cammenga Jörg J Saez Borja B Scadden David T DT Bonifer Constanze C Ye Min M Tenen Daniel G DG

Cancer cell 20131031 5

Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ∼10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. ...[more]

PMID: 24183681

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Project description:Acute myeloid leukemia (AML) propagates as a cellular hierarchy which is maintained by a rare subpopulation of self-renewing leukemia-initiating cells (LICs). These LICs phenotypically resemble HSCs and early myeloid progenitors, and they are functionally defined by their ability to reconstitute AML in xenografted mice. Common transcriptional regulators are believed to drive self-renewal of LICs and normal stem cells. Examples include the histone methyltransferase, MLL and its main targets, the transcription factors HOXA9 and MEIS1; the polycomb group protein, BMI-1; and the Wnt/β-catenin signaling pathway4-9. In AML patients, LICs have been shown to share broad gene expression signatures with hematopoietic stem cells (HSCs) and, in some cases, with embryonic stem cells (ESCs). Moreover, increased expression of these stem cell signatures has been linked to tumor aggressiveness. Elucidating the molecular determinants of stem cell properties in LICs has the potential to improve AML therapy and clarify the relationship between cancer and stem cell biology in general. Here we show that the propagation of LICs in AML depends on Zfx, a transcription factor required for the self-renewal of ESCs and HSCs. Using mouse models, we found that Zfx is required for AML propagation and LIC maintenance. We defined a Zfx-driven gene expression program in murine LICs that correlates with existing stem cell-related gene expression signatures in AML patients. Using a novel, stroma-based RNAi screening strategy, we identified functionally important Zfx target genes. Two of these genes – FAM92A1 and DOCK7 - are required for human AML cell propagation; moreover, their expression levels strongly correlate with AML patient survival across the full spectrum of AML subtypes. Together, our results characterize a novel gene expression program that orchestrates critical stem cell properties of LICs, and drives aggressiveness of AML. Independent primary MLL-AF9 AML cell lines were created carrying the tamoxifen inducible Cre-ER transgene and either the Zfx wild-type (wt/y) (lines 10977, 10980) or the Zfx conditional (Zfx fl/y) allele (lines 10949, 10950, 10986). AML cells generated from each line were isolated from moribund mice and cultured with or without 4-hydroxytamoxifen for 72 hours to induce Cre. After Cre induction, c-Kit + cells were purified by FACS and processed for microarray studies.

Dataset Information

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

Publications

Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia.

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