Suchergebnisse

PMCID: PMC3545406.-- et al. ; The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation. ; National Institutes of Health (NIH) grants NIH CA109335 and NIH CA122105; the Dwoskin Family Foundations; NIH P01 CA34233 FEDER and by MICINN (SAF2009-08803 and SAF2012-32810 to ISG); Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010); MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017); Sandra Ibarra Foundation; Group of Excellence Grant (GR15) from Junta de Castilla y Leon; the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Programme) ; Peer Reviewed

© 2021 Rodríguez-Hernández, Casado-García, Isidro-Hernández, Picard, Raboso-Gallego, Alemán-Arteaga, Orfao, Blanco, Riesco, Prieto-Matos, García Criado, García Cenador, Hock, Enver, Sanchez-Garcia and Vicente-Dueñas. ; ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies. ; Research in CV-D group has been funded by Instituto de Salud Carlos III through the project "PI17/00167" and by a "Miguel Servet Grant" (CPII19/00024—AES 2017–2020), co-funded by European Regional Development Fund/European Social Fund ("A way to make Europe"/"Investing in your future"). Research in the IS-G group is partially supported by FEDER and SAF2015-64420-R MINECO/FEDER, UE, RTI2018-093314-B-I00 MCIU/AEI/FEDER, UE, and by Junta de Castilla y León (UIC-017, CSI001U16, CSI234P18, and CSI144P20). The IS-G lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. CV-D and IS-G have been supported by the German Federal Office for Radiation Protection (BfS)–Germany (FKZ: 3618S32274). IS-G has been supported by the Fundacion Unoentrecienmil (CUNINA project). HH was supported by a Hyundai Hope on Wheels scholar grant. GR-H was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-15). AC-G and MI-H are supported by FSE-Conserjería de Educación de la Junta de Castilla y León 2019 and 2020 (ESF—European Social Fund) fellowship, respectively (REF. CSI067-18 and CSI021-19). JR-G was supported by a scholarship from the University of Salamanca, co-financed by Banco Santander and ESF. SA-A was supported by RTI2018-093314-B-I00 MCIU/AEI/FEDER fellowship (PRE2019-088887).

This article is licensed under a Creative Commons Attribution-NoncommercialNo DerivativeWorks 3.0 Licence. ; Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias. © 2012 European Molecular Biology Organization | All Rights Reserved. ; MICINN (SAF2009-08803 to ISG); Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010 ); MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017); Sandra Ibarra Foundation; Junta de Castilla y Leon; ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program); Obra Social Kutxa; Conserjería de Sanidad de la Junta de Castilla y Leon ; 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 impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL. The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL. We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies. ; J.H. has been supported by the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951), the German Jose Carreras Leukemia Foundation (DJCLS 02R/2016), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Joint funding (Targeting MYC L*10), the Kinderkrebsstiftung (2016/17), and the "Elterninitiative Kinderkrebsklinik e.V. Düsseldorf". SG has been supported by a scholarship of the Hochschule Bonn-Rhein-Sieg. AB 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 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, CSI001U14, 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). ISG Lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. AB and ISG have been supported by the German Carreras Foundation (DJCLS R13/26). IGR was supported by BES-Ministerio de Economía y Competitividad (BES-2013-063789). AML and GRH were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13, CSI001-15). 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), and by the Lady Tata International Award for Research in Leukaemia 2016–2017.