Support of BCP-ALL-cells by autologous bone marrow Th-cells involves induction of AID expression but not widespread AID off-target mutagenesis
Open Access
- 28 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (8), 2275-2289
- https://doi.org/10.1007/s00262-020-02835-x
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.Keywords
Funding Information
- Krebsliga Schweiz (KFS-3958-08-2016-R)
- Heidi Ras Stiftung
- Children’s Research Center (CRC) of the Children’s Hospital Zurich
- Universität Zürich
This publication has 47 references indexed in Scilit:
- The Pediatric Cancer Genome ProjectNature Genetics, 2012
- Mutational Processes Molding the Genomes of 21 Breast CancersCell, 2012
- ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-qPCR quantification cycle (Cq) dataBMC Genomics, 2012
- Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution in BCR-ABL1–Driven B-Cell Lineage Acute Lymphoblastic LeukemiaCancer Research, 2010
- The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid LeukemiaCancer Cell, 2009
- AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH TranslocationsCell, 2008
- Class Switch Recombination and Somatic Hypermutation in Early Mouse B Cells Are Mediated by B Cell and Toll-like ReceptorsImmunity, 2007
- Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1–transformed acute lymphoblastic leukemia cellsThe Journal of Experimental Medicine, 2007
- Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell linesDNA Repair, 2007
- Differential effect of IL-4 and IL-13 on the expression of recombination-activating genes in mature B cells from human peripheral bloodCellular Immunology, 2004