Gene Expression Profiling in Acute Myeloid Leukemia Patient Subgroups With High and Low Sensitivity Toward SYK Inhibitors

Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the uncontrolled proliferation of myeloid cells, and despite recent treatment advances, patient outcomes remain suboptimal. The cytoplasmic spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target in AML due to its role in promoting leukemic cell survival, proliferation, and chemoresistance. This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Our findings revealed significant heterogeneity among patients, leading to the identification of two distinct patient sample groups that were identified as having either high or low sensitivity toward SYK inhibitors. Furthermore, gene expression profiling through RNA sequencing of AML patient samples uncovered 97 significantly differentially expressed genes (DEGs) between the two patient groups with high or low in vitro sensitivity toward SYK inhibitors. Pathway enrichment analyses revealed that the high-sensitivity group was enriched in biological processes related to positive gene regulation and significant pathways included cell adhesion molecules and proteoglycans. In contrast, the low-sensitivity group showed enrichment in pathways related to PI3K-Akt signaling and JAK-STAT signaling. Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML.