4.7 Article

Support of BCP-ALL-cells by autologous bone marrow Th-cells involves induction of AID expression but not widespread AID off-target mutagenesis

Journal

CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 70, Issue 8, Pages 2275-2289

Publisher

SPRINGER
DOI: 10.1007/s00262-020-02835-x

Keywords

B-cell precursor acute lymphoblastic leukemia; T-helper cells; Activation-induced cytidine deaminase; Mutational signature

Funding

  1. Universitat Zurich
  2. Krebsliga Schweiz/Swiss Cancer League [KFS-3958-08-2016-R]
  3. Children's Research Center (CRC) of the Children's Hospital Zurich
  4. Heidi-Ras Stiftung

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. Research suggests that Th-cell-induced AID expression may play a role in the pathogenesis, but in actual patients, the contribution of AID remains unclear.
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-kappa B and TGF beta/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.

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