Integration of Metabolic Profiling and Functional Genomics Suggests IGJ as a Driver of Chemoresistance in B-ALL.

[BACKGROUND] B-cell precursor acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy characterized by the uncontrolled proliferation of immature B lymphoblasts. Despite significant advancements in treatment, chemoresistance remains a major challenge. Previous studies, including those involving Colombian patient cohorts, have identified a gene signature involving ID1, ID3, and IGJ, which correlates with poor prognosis; however, the underlying mechanisms remain unclear. This study integrates metabolic profiling with gene expression analysis of ID1, ID3, and IGJ in patient-derived lymphoblasts. It explores the role of IGJ overexpression in NALM-6 cells to assess its potential contribution to chemoresistance.

[METHODS] Bone marrow samples from 33 newly diagnosed B-ALL patients were analyzed for ID1, ID3, and IGJ gene expression. Seahorse XF metabolic assays were conducted on 13 patient samples to assess mitochondrial respiration and glycolytic function. Functional studies were performed in the NALM-6 B-ALL cell line using CRISPRa-mediated IGJ overexpression, followed by metabolic and chemoresistance assays using resazurin-based viability testing with key chemotherapeutic agents.

[RESULTS] Patient-derived lymphoblasts exhibited a quiescent metabolic phenotype, with two distinct metabolic subgroups based on oxygen consumption and glycolysis rates. Higher IGJ expression was significantly associated with the glycolytic subgroup and correlated with worse event-free survival (EFS, p = 0.0179) and overall survival (OS, p = 0.0205). In NALM-6 cells, IGJ overexpression led to increased metabolic activity and conferred resistance to dexamethasone, cytarabine, doxorubicin, and methotrexate, but not cyclophosphamide.

[CONCLUSION] IGJ upregulation promotes metabolic reprogramming and chemoresistance in B-ALL, suggesting a potential role for IGJ as a biomarker and therapeutic target in overcoming treatment resistance. These findings provide new insights into the metabolic mechanisms underlying B-ALL progression and highlight IGJ as a candidate for future targeted interventions.