Distinct transcriptomic signatures in non-hispanic black AML patients with NPM1 mutations reveal potential drivers of poor prognosis

Abstract Introduction: Non-Hispanic Black (NHB) patients with Acute Myeloid Leukemia (AML) harboring NPM1 mutations (NPM1c), despite being categorized as favorable risk by the ELN 2022 risk classifier, have poor overall survival compared to Non-Hispanic White (NHW) NPM1c patients. The molecular mechanisms driving this disparity remain underexplored. Therefore, our objective was to identify differentially expressed genes (DEG) in NHB patients with NPM1c mutations when compared to NHW NPM1c patients to better understand the molecular mechanisms behind this disparity. Methods: We analyzed RNA-sequencing data of 1,870 patients across four publicly available datasets BEAT AML (2018, 2022), TCGA and GSE137851 identifying 327 NHW and 17 NHB patients with NPM1c mutations. The RNA seq data was batch corrected to remove any technical variability before differential expression analysis using DESeq2. DEGs with FDR<0.05 were filtered to exclude DEGs present in NHB patients with NPM1 wildtype AML. The curated list of distinct genes was subjected to Gene Set Enrichment Analysis (GSEA) using Gene ontology (GO) and KEGG databases. Results: We identified 123 distinct DEG in NHB patients with NPM1c in comparison to NHW NPM1c patients, including 8 upregulated and 115 downregulated genes. Of the downregulated genes, KDR and NTRK2 interact with MAPK/ERK pathway which was recently shown to interact with NPM1. When survival by gene expression level was assessed using OncoLnc low expressors of both KDR and NTRK2 had a significantly worse survival. Among upregulated genes, SAP30 was one of the top scoring genes and represses gene expression through histone deacetylation. GSEA analysis with the GO database using the entire DEG list showed significant negative regulation of proliferation, differentiation and metabolic pathways. Conclusion: Our RNA-seq differential expression analysis identified a distinct set of DEGs in NHB AML patients with NPM1c. Top candidates for further characterization include SAP30, NTRK2, and KDR. Whether these genes mechanistically contribute to chemoresistance and poor survival is currently being investigated. If validated these genes could serve as biomarkers for poor risk NHB patients with NPM1 mutated AML.