Suchergebnisse

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, p19ArfRag1 (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. ; J. Hauer has been supported by the German Cancer Foundation (110997), DJCLS02R/2016, KKS A2016/07 and from the "Forschungskommission" of the medical faculty of the Heinrich Heine University. A. Borkhardt has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in I. Sánchez-García's group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001 U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente and by the ARIMMORA project (European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). I. Sánchez-García's lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A. Borkhardt and I. Sánchez-García have been supported by the German Carreras Foundation (DJCLS R13/26). Research in C. Vicente-Dueñas' group is partially supported by a "Miguel Servet" Grant (CP14/00082 - AES 2013-2016 - FEDER) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad) and by the Lady Tata International Award for Research in Leukaemia 2016-2017. A. Martín-Lorenzo was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13). ; Peer Reviewed

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development. ; Research in CVD group is partially supported by FEDER, "Miguel Servet" Grant (CP14/00082 - AES 2013–2016) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad), "Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III" (PI17/00167). J.H. has been supported by ERAPer Med, the German Cancer AID (Translational Oncology Program 70112951), the DKTK German Cancer Consortium Joint funding program "Targeting MYC" L*10, The German Jose Carreras Foundation (DJCLS 02R/2016), and the Kinderkrebsstiftung (2016/17). A.R.R. was supported by ERC StG BCLYM-207844, SAF2013-42767-R and SAF2016-75511-R grants and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). P.D. was funded by the Asociación Española Contra el Cancer. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by SAF2015-64420-R MINECO/FEDER, UE, RTI2018-093314-B-I00 MCIU/AEI/FEDER, UE, by Junta de Castilla y León (UIC-017, CSI001U16, and CSI234P18). I.S.G. lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A.B. and I.S.G. have been supported by the German Carreras Foundation (DJCLS R13/26) and by the German Federal Office for Radiation Protection (BfS)-Germany (FKZ: 3618S32274). G.R.H., A.C.-G and S.G.T.D. were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-15, CSI067-18 and CSI003-17, respectively). F.A. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (AU 525/1-1). ; Peer reviewed

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development. ; Research in CVD group is partially supported by FEDER, "Miguel Servet" Grant (CP14/00082 - AES 2013–2016) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad), "Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III" (PI17/00167). J.H. has been supported by ERAPer Med, the German Cancer AID (Translational Oncology Program 70112951), the DKTK German Cancer Consortium Joint funding program "Targeting MYC" L*10, The German Jose Carreras Foundation (DJCLS 02R/2016), and the Kinderkrebsstiftung (2016/17). A.R.R. was supported by ERC StG BCLYM-207844, SAF2013-42767-R and SAF2016-75511-R grants and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). P.D. was funded by the Asociación Española Contra el Cancer. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by SAF2015-64420-R MINECO/FEDER, UE, RTI2018-093314-B-I00 MCIU/AEI/FEDER, UE, by Junta de Castilla y León (UIC-017, CSI001U16, and CSI234P18). I.S.G. lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A.B. and I.S.G. have been supported by the German Carreras Foundation (DJCLS R13/26) and by the German Federal Office for Radiation Protection (BfS)-Germany (FKZ: 3618S32274). G.R.H., A.C.-G and S.G.T.D. were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-15, CSI067-18 and CSI003-17, respectively). F.A. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (AU 525/1-1). ; Sí