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.

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Background: Glomerulosclerosis is a characteristic pathologic feature in chronic kidney disease (CKD). Convincing evidence indicates that the mesangial cells (MCs) play critical role in this process. However, the exact mechanism remains unclear. Using RNA-seq analysis, we previously found that lncRNA uc.412 was involved in the MC proliferation. Here, the effect of uc.412 on glomerular fibrosis and the potential mechanism were explored. Methods: In vivo, CKD mice models were established by 5/6 nephrectomy. The expression of lncRNA uc.412 in CKD was detected by Real-Time PCR. In vitro, MCs were intervened with TGF-β1 (10ng/mL). The uc.412 expression in MCs was detected by in site hybridization. MCs were transfected with uc.412 siRNA or a lentivirus targeting uc.412 and then examined using western blot, Real-Time PCR, RNA pull down assay and immunofluorescence staining. Results: We found that the expression of uc.412 was significantly increased in CKD mice and is induced by TGF-β1 via Smad3- dependent signal pathway. Overexpressing uc.412 caused MCs fibrosis and knockdown of uc.412 alleviated TGF-β1-induced MCs fibrosis. Using RNA pull down analysis, we found that the ELAVL1 was the specific binding protein for uc.412. Moreover, ELAVL1 expression was increased in TGF-β1-treated MCs and silencing ELAVL1 expression attenuated MCs fibrosis. Conclusions: Thus, here, we demonstrated that uc.412, which is regulated in a Smad3-dependent mechanism, is significantly increased during progression of CKD via regulating ELAVL1 expression. Our findings provided the therapeutic strategy for treatment of CKD.