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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

ABSTRACT: Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

PROVIDER: PRJNA942922 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23770302_1.fastq.gz	Fastqsanger.gz
	SRR23770302_2.fastq.gz	Fastqsanger.gz
	SRR23770303_1.fastq.gz	Fastqsanger.gz
	SRR23770303_2.fastq.gz	Fastqsanger.gz
	SRR23770304_1.fastq.gz	Fastqsanger.gz

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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [ChIP-Seq]

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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [RNA-Seq]

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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [RNA-Seq]

Project description:In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knock-out (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin inhibitor) and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.

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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1 [ChIP-Seq]

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Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

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Mutant NPM1 marginally impacts translation in AML cells

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Detection of mutant NPM1 mRNA in acute myeloid leukemia (AML) using custom gene expression arrays [Validation cohort]

Project description:Abstract Mutations in the gene encoding nucleophosmin (NPM1) carry prognostic value for patients with acute myeloid leukemia (AML). Various techniques are currently being used to detect these mutations in routine molecular diagnostics. Incorporation of accurate NPM1 mutation detection on a gene expression platform would enable simultaneous detection with various other expression biomarkers. Here we present an array based mutation detection using custom probes for NPM1 WT mRNA and NPM1 type A, B, and D mutant mRNA. This method was 100% accurate on a training cohort of 505 newly diagnosed unselected AML cases. Validation on an independent cohort of 143 normal karyotype AML cases revealed no false negative results, and one false positive (sensitivity 100.0%, and specificity 98.7%). Based on this, we conclude that this method provides a reliable method for NPM1 mutation detection. The method can be applied to other genes/mutations as long as the mutant alleles are sufficiently high expressed. Validation cohort of 143 AML cases analyzed using the AMLprofiler

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Detection of mutant NPM1 mRNA in acute myeloid leukemia (AML) using custom gene expression arrays [Training cohort]

Project description:Abstract Mutations in the gene encoding nucleophosmin (NPM1) carry prognostic value for patients with acute myeloid leukemia (AML). Various techniques are currently being used to detect these mutations in routine molecular diagnostics. Incorporation of accurate NPM1 mutation detection on a gene expression platform would enable simultaneous detection with various other expression biomarkers. Here we present an array based mutation detection using custom probes for NPM1 WT mRNA and NPM1 type A, B, and D mutant mRNA. This method was 100% accurate on a training cohort of 505 newly diagnosed unselected AML cases. Validation on an independent cohort of 143 normal karyotype AML cases revealed no false negative results, and one false positive (sensitivity 100.0%, and specificity 98.7%). Based on this, we conclude that this method provides a reliable method for NPM1 mutation detection. The method can be applied to other genes/mutations as long as the mutant alleles are sufficiently high expressed. Training cohort of 505 AML cases analyzed using the AMLprofiler

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