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An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML (RNA-Seq)

ABSTRACT: An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML (RNA-Seq)

PROVIDER: PRJNA1055693 | ENA |

REPOSITORIES: ENA

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An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML

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An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML (CUT&RUN)

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An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML

Project description:Differentiation therapy has proven to be curative for the rare acute myeloid leukemia (AML) subtype, the acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3β kinase (GSK3βi) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway (IFN-I) via inducing expression of IRF7 (LSD1i) and b-catenin (GSK3i) and their selective co-occupancy at targets such as STAT1, which is necessary for combination-indued differentiation. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and cell cycle genes. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy re-wires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.

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Project description:While most current therapies for acute myeloid leukemia (AML) suffer from limited efficacy and substantial toxicity, differentiation therapy has proven to be curative for the rare AML subtype, acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3β kinase (GSK3βi) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination treatment induces selective co-occupancy of IRF7 and b-catenin at promoters of the type I interferon signaling pathway component genes such as STAT1 essential for AML differentiation, and key downstream target genes, and consequently their expression. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and activates a pro-differentiation transcription program. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy re-wires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.

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