Activation-induced cytidine deaminase prevents pro-B cell acute lymphoblastic leukemia by functioning as a negative regulator in Rag1 deficient pro-B cells

// Franziska Auer 1 , Deborah Ingenhag 1 , Stefan Pinkert 1 , Sven Kracker 2,3 , Salima Hacein-Bey-Abina 4,5 , Marina Cavazzana 2,3 , Michael Gombert 1 , Alberto Martin-Lorenzo 6,7 , Min-Hui Lin 1 , Carolina Vicente-Duenas 7 , Isidro Sanchez-Garcia 6,7 , Arndt Borkhardt 1 and Julia Hauer 1 1 Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, Duesseldorf, Germany 2 Universite Paris Descartes, Sorbonne Paris Cite, Imagine Institute, Paris, France 3 INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, Paris, France 4 UTCBS CNRS UMR 8258, INSERM U1022, Faculte de Pharmacie de Paris, Universite Paris Descartes, Sorbonne Paris Cite, Chimie Paris-Tech, Paris, France 5 Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hopital Kremlin-Bicetre, Assistance Publique-Hopitaux de Paris, Le-Kremlin-Bicetre, France 6 Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain 7 Institute of Biomedical Research of Salamanca, Salamanca, Spain Correspondence to: Julia Hauer, email: // Keywords : acute lymphoblastic leukemia, activation induced cytidine deaminase, pro-B cells, Rag1 deficiency Received : July 27, 2017 Accepted : July 31, 2017 Published : September 07, 2017 Abstract Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D)J-recombination, we utilized an in vivo model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, p19Arf -/- Rag1 -/- (AR) mice were crossed with Aid-deficient mice (ARA). Surprisingly, loss of Aid expression in pro-B cells accelerated pro-B ALL incidence from 30% (AR) to 98% (ARA). This effect was Aid dose dependent, since Aid +/- animals of the same background displayed a significantly lower incidence (83%). Furthermore, B-cell-specific Aid up-regulation was observed in Aid-competent pro-B ALLs. Additional whole exome/sanger sequencing of murine pro-B ALLs revealed an accumulation of recurrent somatic Jak3 (p.R653H, p.V670A) and Dnm2 (p.G397R) mutations, which highlights the importance of active IL7R signaling in the pro-B ALL blast cells. These findings were further supported by an enhanced proliferative potential of ARA pro-B cells compared to Aid-competent cells from the same genetic background. In summary, we show that both Aid and Rag1 act as a negative regulators in pro-B cells, preventing pro-B ALL.