Abstract
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFβ/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects.
Highlights
Materials and methodsB-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common pediatric malignancy [1], arises from the expansion of precursor B-cells in the bone marrow (BM)
AICDA expression for each patient and mean ± SD are shown. p values were calculated using one-way ANOVA with Tukey correction for multiple comparison. p > 0.05 not significant (n.s.), b–d Values of each patient and median values are shown. b Relative contribution of mutational signatures to mutations in total genome was assessed using R package MutationalPatterns in wholegenome sequencing (WGS) data. c Cosine similarity of original mutation profile compared to the reconstructed mutation profile. d Relative contribution of mutational signatures to clustered mutations is shown for patients with cosine similarity > 0.75
Relative contribution in patient SJBALL021373 is depicted in red. e Rainfallplot of mutations in patient SJBALL021373 was generated using R package karyoploteR. f Table of genes with most mutations in AID motif (RC > NY). p values were calculated using Fisher’s exact test by comparing observed mutations (nmut in RCY) to expected AID motif mutations for each gene according to the frequency of AID motif in each gene (% RCY in gene)
Summary
Materials and methodsB-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common pediatric malignancy [1], arises from the expansion of precursor B-cells in the bone marrow (BM). The first step is characterized by chromosomal aberrations with prenatal origin, such as ETV6-RUNX1 [3]. This translocation is present in 1–5% of newborns but only 1% thereof develop overt leukemia [4], i.e., after the acquisition of secondary mutations. Both epidemiological and recent mechanistic studies suggest that a delayed exposure to common infections is involved in the second step [2, 5, 6]. At a later stage of BCP-ALL, additional mutagenesis may induce mutations associated with therapy resistance [7]. The precise mechanisms leading to secondary and therapy resistance-associated mutations are unclear
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