Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes

Abstract

Abstract The human kinome, which comprises >500 kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndromes (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified 7 kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the kinase stratification score (KISS) by combining the weighted expressions of the 7 kinases and validated its prognostic significance in 2 external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for gene sets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.