RNA-seq analysis of NRAS-mutant MV-4-11 AML cells treated with gilteritinib, clofarabine, or combined gilteritinib and clofarabine

To define transcriptional programs associated with NRAS-driven FLT3 inhibitor resistance and the rationale for targeting ribonucleotide reductase, we performed RNA-seq in MV-4-11 FLT3-ITD AML cells expressing NRAS WT, NRAS G12C, or NRAS Q61K and treated with vehicle, gilteritinib, clofarabine, or the combination of gilteritinib and clofarabine.

Differential expression and gene set enrichment analyses were used to evaluate RNR-associated nucleotide synthesis, MYC/E2F, DNA replication, cell-cycle, and DNA damage/repair programs. These data show that NRAS-mutant cells maintain replication- and nucleotide-supply-associated transcriptional programs under FLT3 inhibition, supporting an RAS-RNR axis that contributes to FLT3 inhibitor resistance in AML.