The Role and Function of a Novel Signature Gene in BCR::ABL1 (Ph) B-cell Acute Lymphoblastic Leukemia

PROJECT SUMMARY Philadelphia chromosome (Ph)-positive and Ph-like B-cell acute lymphoblastic leukemia (B-ALL) are high-risk leukemia subtypes with poor long-term survival rates. Despite advances in treatment, patients with these subtypes continue to have survival rates below 50%. Our research aims to address this urgent need by focusing on a novel hallmark gene, AL021978.1 (hereafter named A978), which is identified as the most significantly overexpressed gene in Ph/Ph-like B-ALL. Our preliminary data indicate that A978 encodes a short protein located in mitochondria, promoting leukemic cell proliferation, and contributing to resistance against tyrosine kinase inhibitors (TKIs). The long-term objective of this project is to improve treatment outcomes for patients with Ph/Ph-like B-ALL. Our specific aims are: 1) to determine the biological effects of A978 in leukemic cells; 2) to study the effects and functions of A978 in mitochondria and metabolic activities; and 3) to evaluate the therapeutic impact of pharmacologically inhibiting A978 in Ph B-ALL. To achieve these aims, we will use a combination of in vitro and in vivo models, including B-ALL cell lines and patient-derived xenograft models. We will employ a variety of techniques, such as RNA sequencing (RNA- seq), single-cell RNA-seq, BioID and mass spectrometry, and metabolomic profiling, to explore the molecular functions and biological pathways regulated by A978. Additionally, we will develop and evaluate a therapeutic strategy using a CpG-conjugated small interfering RNA to specifically silence A978 expression in leukemic cells. The significance of this project lies in its potential to uncover new mechanisms driving the proliferation and progression of high-risk B-ALL subtypes. By targeting A978, we aim to develop novel therapeutic strategies that can be combined with existing treatments to enhance their efficacy. This research is expected to largely advance our understanding of Ph/Ph-like B-ALL and contribute to the development of more effective treatments, ultimately improving survival rates for patients with these high-risk leukemias.