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

作者：Auer Franziska; Ingenhag Deborah; Pinkert Stefan; Kracker Sven; Hacein Bey Abina Salima; Cavazzana Marina; Gombert Michael; Martin Lorenzo Alberto; Lin Min Hui; Vicente Duenas Carolina; Sanchez Garcia Isidro; Borkhardt Arndt; Hauer Julia^*

来源：Oncotarget, 2017, 8(44): 75797-75807.

DOI：10.18632/oncotarget.20563

• acute lymphoblastic leukemia
• activation induced cytidine deaminase
• pro-B cells
• Rag1 deficiency

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.

• 出版日期2017-9-29