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RNA-seq analysis of transcriptomic changes in WT and MPHOSPH8 KO MOLM-13 leukemia cells

ABSTRACT: Human cancers including acute myeloid leukemia (AML) hijack epigenetic machinery to drive malignant self-renewal, whereas dysregulated epigenetic states also create selective and targetable liabilities. We performed domain-based CRISPR/Cas9 screens of human chromatin regulators and identified MPHOSPH8 (or MPP8), a component of the HUSH complex and repressor of LINE-1 retrotransposons, as a selective epigenetic dependency of AML cells. While dispensable for normal hematopoiesis, MPP8 loss inhibited AML initiation and maintenance by reactivating LINE-1 retrotransposons. Activation of endogenous or ectopic LINE-1 photocopied MPP8 loss, whereas blocking LINE-1 retrotransposition abrogated MPP8-deficiency-induced phenotypes. Reactivated LINE-1 retrotransposition increased DNA damage, activated cyclin-dependent kinase inhibitor p21 (or CDKN1A), and induced AML differentiation. Enhanced L1 suppression in AML stem cells is associated with therapy resistance and poor prognosis. Hence, while retrotransposons are historically recognized as sources of genetic instability and somatic mutations, we uncover an unexpected role for HUSH/MPP8 in promoting cancer by suppressing genomic transposable elements.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150982 | GEO | 2021/02/01

REPOSITORIES: GEO

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