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

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

PROVIDER: PRJNA1051076 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27175634.fastq.gz	Fastqsanger.gz
	SRR27175635.fastq.gz	Fastqsanger.gz
	SRR27175636.fastq.gz	Fastqsanger.gz
	SRR27175637.fastq.gz	Fastqsanger.gz
	SRR27175638.fastq.gz	Fastqsanger.gz

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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:The paper describes a model of acute myeloid leukaemia. Created by COPASI 4.26 (Build 213) This model is described in the article: Optimal control of acute myeloid leukaemia Jesse A. Sharp, Alexander P Browning, Tarunendu Mapder, Kevin Burrage, Matthew J Simpson Journal of Theoretical Biology 470 (2019) 30–42 Abstract: Acute myeloid leukaemia (AML) is a blood cancer affecting haematopoietic stem cells. AML is routinely treated with chemotherapy, and so it is of great interest to develop optimal chemotherapy treatment strategies. In this work, we incorporate an immune response into a stem cell model of AML, since we find that previous models lacking an immune response are inappropriate for deriving optimal control strategies. Using optimal control theory, we produce continuous controls and bang-bang controls, corre- sponding to a range of objectives and parameter choices. Through example calculations, we provide a practical approach to applying optimal control using Pontryagin’s Maximum Principle. In particular, we describe and explore factors that have a profound influence on numerical convergence. We find that the convergence behaviour is sensitive to the method of control updating, the nature of the control, and to the relative weighting of terms in the objective function. All codes we use to implement optimal control are made available. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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