Faculty Collaboration Database

Combinatorial genetics reveals the Dock1-Rac2 axis as a potential target for the treatment of NPM1;Cohesin mutated AML. Leukemia 2022 Aug;36(8):2032-2041

Date

07/02/2022

Pubmed ID

35778533

Pubmed Central ID

PMC9357218

DOI

10.1038/s41375-022-01632-y

Scopus ID

2-s2.0-85133226227 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

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 have 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 Npm1^cAflox/+ and core cohesin subunit Smc3^flox/+ mice to examine AML development. While Npm1^cA/+;Smc3^Δ/+ mice developed AML with a similar latency and penetrance as Npm1^cA/+ mice, RNA-seq suggests that the Npm1^cA/+; Smc3^Δ/+ mutational combination uniquely alters the transcriptome. We found that the Rac1/2 nucleotide exchange factor Dock1 was specifically upregulated in Npm1^cA/+;Smc3^Δ/+ HSPCs. Knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis only in Npm1^cA/+;Smc3^Δ/+ AML. Higher Rac activity was also observed in Npm1^cA/+;Smc3^Δ/+ vs. Npm1^cA/+ AMLs. Importantly, the Dock1/Rac pathway is targetable in Npm1^cA/+;Smc3^Δ/+ AMLs. Our results suggest that Dock1/Rac represents a potential target for the treatment of patients harboring NPM1cA and cohesin mutations and supports the use of combinatorial genetics to identify novel precision oncology targets.

Author List

Meyer AE, Stelloh C, Pulakanti K, Burns R, Fisher JB, Heimbruch KE, Tarima S, Furumo Q, Brennan J, Zheng Y, Viny AD, Vassiliou GS, Rao S

Authors

Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Sergey S. Tarima PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Leukemia, Myeloid, Acute
Mice
Mutation
Nuclear Proteins
Precision Medicine
Transcription Factors
rac GTP-Binding Proteins