Oncotarget

Research Papers:

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, Deborah Ingenhag, Stefan Pinkert, Sven Kracker, Salima Hacein-Bey-Abina, Marina Cavazzana, Michael Gombert, Alberto Martin-Lorenzo, Min-Hui Lin, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt and Julia Hauer _

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Oncotarget. 2017; 8:75797-75807. https://doi.org/10.18632/oncotarget.20563

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Abstract

Franziska Auer1, Deborah Ingenhag1, Stefan Pinkert1, Sven Kracker2,3, Salima Hacein-Bey-Abina4,5, Marina Cavazzana2,3, Michael Gombert1, Alberto Martin-Lorenzo6,7, Min-Hui Lin1, Carolina Vicente-Dueñas7, Isidro Sánchez-García6,7, Arndt Borkhardt1 and Julia Hauer1

1 Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, Duesseldorf, Germany

2 Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France

3 INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, Paris, France

4 UTCBS CNRS UMR 8258, INSERM U1022, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Chimie Paris-Tech, Paris, France

5 Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France

6 Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, 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.


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