Targeting IKZF1 via HDAC1: Combating Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) accounts for 1.3% of all cancers, with a limited survival of only 30%, and treating AML is a continuous challenge in medicine. IKZF1 is a DNA-binding protein that is highly mutated and undruggable but significant in causing AML. The current study aims to target its transcription factors (TFs) modulating IKZF1 activity. The TF network was constructed and analyzed which revealed a dense Markov cluster (MCL) cluster and five hub genes namely, HDAC1, EP300, CREBBP, TP53, and MYC; the first node clusters were generated for the hub genes. Functional enrichment analysis found AML pathway enriched in all the clusters. Gene ontology terms were majorly related to transcription regulation terms including RNA polymerase transcription regulation, DNA binding activity, DNA templated transcription, and transcription factor binding. Further, the mutation profile of all the TFs found HDAC1 with a very low mutation profile of 0.1% and the survival plot found HDAC1 with a hazard ratio of 1.17 with increased survival upon low expression. Also, among the hub genes, HDAC1 was the only first node interactor with IKZF1. Thus, HDAC1 could be a potential biomarker candidate as well as a key target in treating AML. Insight Box The study has an integrated approach for identifying a potential target through network analysis, functional enrichment analysis, mutation profiling survival prognosis, and target screening. The study employs a better strategy for targeting IKZF1, a significantly upregulated gene in AML by regulating its transcription factors. The analysis revealed a network of TFs regulating IKZF1, among which HDAC1 emerged as a promising candidate due to its low mutation rate, association with better survival outcomes, and direct interaction with IKZF1. This suggests HDAC1 could be a valuable biomarker and therapeutic target for AML treatment.