Molecular Characterization of the Response to Conventional Chemotherapeutics in Pro-B-ALL Cell Lines in Terms of Tumor Relapse

Little is known about optimally applying chemotherapeutic agents in a specific temporal sequence to rapidly reduce the tumor load and to improve therapeutic efficacy. The clinical optimization of drug efficacy while reducing side effects is still restricted due to an incomplete understanding of the mode of action and related tumor relapse mechanisms on the molecular level. The molecular characterization of transcriptomic drug signatures can help to identify the affected pathways, downstream regulated genes and regulatory interactions related to tumor relapse in response to drug application. We tried to outline the dynamic regulatory reprogramming leading to tumor relapse in relapsed MLL-rearranged pro-B-cell acute lymphoblastic leukemia (B-ALL) cells in response to two first-line treatments: dexamethasone (Dexa) and cytarabine (AraC). We performed an integrative molecular analysis of whole transcriptome profiles of each treatment, specifically considering public knowledge of miRNA regulation via a network-based approach to unravel key driver genes and miRNAs that may control the relapse mechanisms accompanying each treatment. Our results gave hints to the crucial regulatory roles of genes leading to Dexa-resistance and related miRNAs linked to chemosensitivity. These genes and miRNAs should be further investigated in preclinical models to obtain more hints about relapse processes.

Automated summary

The optimal application of chemotherapeutic agents in a specific temporal sequence to rapidly reduce tumor load and improve therapeutic efficacy is still poorly understood. Clinical optimization of drug efficacy is restricted by an incomplete understanding of molecular mechanisms and tumor relapse. Transcriptomic drug signatures and network-based approaches can help identify key driver genes and miRNAs that control relapse mechanisms. Studying genes and miRNAs involved in Dexa-resistance and chemosensitivity may provide insights into tumor relapse processes.