SRA

Acute myeloid leukemia (AML) is driven by mutations that occur in numerous combinations. A better understanding of how mutations interact with one another to cause disease is critical to developing targeted therapies. Approximately 50% of patients that harbor a common mutation in NPM1 (NPM1cA) also harbor a mutation in the cohesin complex. As cohesin and Npm1 are known to regulate gene expression, we sought to determine how cohesin mutation alters the transcriptome in the context of NPM1cA. We utilized inducible Npm1cAflox/+ and Smc3flox/+ mouse models to examine this genetic interaction. While Npm1cA/+;Smc3 /+ mice developed AML with similar latency as Npm1cA/+ mice, RNA sequencing suggests that the Npm1cA; Smc3 /+ mutational combination uniquely alters the transcriptome. We found that the Rac1/2 nucleotide exchange factor Dock1 was uniquely upregulated in Npm1cA/+;Smc3 /+ HSPCs. Knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis specifically in Npm1cA/+;Smc3 /+ AML. Higher Rac activity was also observed in Npm1cA/+;Smc3 /+ vs. Npm1cA/+ AMLs. Importantly, the Dock1/Rac pathway is targetable in Npm1cA/+;Smc3 /+ AMLs. Our results suggest that Dock1/Rac represent unique targets for the treatment of patients harboring both the NPM1cA and cohesin mutations and support the use of combinatorial genetics to identify novel precision oncology targets. Overall design: RNA-seq of 4 conditions, 3 replicates each