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Transcriptional profiling of leukemic stem cells of AML treated with Wnt inhibitors in vivo

ABSTRACT: Epigenetic changes in cancerous cells including alterations in histone methylation facilitate the installation of growth-promoting signaling networks by altering DNA accessibility to transcriptional machinery. The oncofusion protein MLL-AF9 promotes deviant histone methylation and induces acute myelogenous leukemia (AML) in animals. Despite observations supporting a role for WNT signaling in AML pathogenesis, we have a limited mechanistic account of how cancerous growth is sustained in this context. Using chemical antagonists of WNT signaling and genetic ablation of the WNT chaperone Wntless (Wls), we identified the homeobox domain gene Sine oculis 1 (Six1) to be an atypical WNT-controlled target gene in MLL-AF9-transformed leukemic stem cells (LSCs). Elimination of Wls or Six1 in MLL-AF9 LSCs, or their exposure to WNT pathway inhibitors results in extended survival in LSC-transplanted recipient mice suggesting that WNT/SIX1 signaling is critical to MLL-AF9 transformation. Profiling of chromatin accessibility changes using ATAC-seq of MLL-AF9 transformed cells reveals chromatin remodeling in Six1 DNA regions that support binding of the transcriptional effector TCF7L2. Our data suggests de novo installation of a WNT/SIX1 signaling axis is critical to the development of some forms of AML and reveals how epigenetic alterations can re-assemble master regulatory pathways controlling cell fate with cancer-promoting consequences.

ORGANISM(S): Mus musculus

PROVIDER: GSE111275 | GEO | 2018/03/05

REPOSITORIES: GEO

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Profiling of chromatin accessibility by ATAC-seq in hematopoietic LSK cells and leukemic stem cells of AML

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