DEAPR: Differential Expression and Pathway Ranking Tool Demonstrates NRAS^G12V and NRAS^G12D Mutations Have Differing Effects in THP-1 Cells

Background/Objectives: NRAS mutations are found in approximately 10% of patients with acute myeloid leukemia (AML), with nearly half of those occurring at codon 12, but little is known about how differing G12 mutants affect cancer cell activity. Methods: A novel bioinformatic technique, differential expression and pathway ranking (DEAPR), was used to identify the most prominent changes in terms of both individual genes and associated pathways when comparing AML THP-1 cells containing an NRAS^G12D mutation with B11 cells, which are THP-1-derived cells with the NRAS^G12D allele removed and a dox-inducible NRAS^G12V allele introduced. Results: In total, 1456 differentially expressed (DE) protein-coding genes were uniquely associated to the NRAS^G12D mutation, while 585 DE protein-coding genes were specific to the NRAS^G12V mutation. The innate immune system pathway was prominent in both mutant-specific lists, even though the genes involved were not in both lists. Furthermore, the two calprotectin genes (S100A8 and S100A9), also associated with innate immunity, were upregulated in the NRAS^G12D mutant and downregulated in the NRAS^G12V mutant. Conclusions: This study, using the DEAPR strategy, clearly demonstrates the dramatic changes associated with two seemingly similar NRAS mutations, suggesting the deployment of different treatment strategies based on the type of NRAS mutation present.