Targeting BACH2-FOS signaling overcomes chemoresistance via stromal microenvironment alterations in pediatric acute lymphoblastic leukemia

Abstract

Background Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about the function and regulatory network of BACH2 in pediatric ALL (p-ALL). Methods We analyzed the clinical relevance of BACH2 in nearly 450 published p-ALL microarray data. The mRNA and protein levels of BACH2 were validated in an independent cohort of p-ALL samples. The roles of BACH2 in leukemogenesis were examined using cell growth and proliferation assays, cell cycle and BrdU assays, cell apoptosis and cell adhesion assays as well as in vivo mouse models. Multiplexed flow cytometric assay was utilized to detect the bone marrow environmental alterations. Luciferase activity assay and CUT&Tag sequencing were applied to determine the downstream target of BACH2. The therapeutic effects of chemicals were evaluated in precursor B (pre-B) ALL cells, primary p-ALL cells and in vivo pre-B ALL-driven leukemia xenografts. Results We found aberrant BACH2 expression at newly diagnosis not only facilitated risk stratification of p-ALL but also served as a sensitive predictor for early treatment response and clinical outcome. Silencing BACH2 in pre-B ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred chemo-resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of cytarabine treatment in both primary p-ALL cells and pre-B ALL-driven leukemia xenografts and prolonged survival of tumor-bearing mice. Conclusions Our results highlight an interconnected network of BACH2-FOS, disruption of which could render current ALL chemotherapies more effective and offer a promising therapeutic strategy to overcome chemoresistance in p-ALL.