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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\/<jats:italic>AICDA<\/jats:italic>) 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 <jats:italic>AICDA<\/jats:italic> 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-\u03baB and TGF\u03b2\/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.<\/jats:p>","DOI":"10.1007\/s00262-020-02835-x","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T10:44:04Z","timestamp":1611830644000},"page":"2275-2289","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Support of BCP-ALL-cells by autologous bone marrow Th-cells involves induction of AID expression but not widespread AID off-target mutagenesis"],"prefix":"10.1007","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9193-5586","authenticated-orcid":false,"given":"Sabrina","family":"Traxel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3717-7603","authenticated-orcid":false,"given":"Julia","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Richard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-664X","authenticated-orcid":false,"given":"Semjon","family":"Sidorov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-3712","authenticated-orcid":false,"given":"Felix","family":"Niggli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-8804","authenticated-orcid":false,"given":"Christoph","family":"Berger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2712-1374","authenticated-orcid":false,"given":"David","family":"Nadal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3238-5120","authenticated-orcid":false,"given":"Simone","family":"B\u00fcrgler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"2835_CR1","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/S0140-6736(08)60457-2","volume":"371","author":"C-H Pui","year":"2008","unstructured":"Pui C-H, Robison LL, Look AT (2008) Acute lymphoblastic leukaemia. 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The use of bone marrow mononuclear cells from leukemia patients and palatine tonsils from children undergoing routine tonsillectomy was approved by the regional ethics committee (Kantonale Ethikkommision Z\u00fcrich, KEK-ZH Nr. StV 40\/05 and KEK-ZH Nr. 2014- 0701).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The guardians of all subjects gave informed consent for the use of samples.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}