RESUMEN
B-cell Acute Lymphoblastic Leukemia (B-ALL) is the most common pediatric cancer, arising most often in children aged 2-5 years. This distinctive age distribution hints at an association between B-ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B-ALL surpass 90% in high-income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution of B-ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B-ALL and explores how this knowledge can inform preventive strategies.
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The prevalence of childhood B cell acute lymphoblastic leukemia (B-ALL) is increasing, particularly in developed countries. There is no clear explanation for this increment, but recent data suggest that, besides genetic predisposition, stress in the immune system (e.g., an infection) might have an important role in B-ALL leukemogenesis. Here, we speculate on how this knowledge might impact B-ALL prevention strategies.
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Leucemia de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Predisposición Genética a la Enfermedad , HumanosRESUMEN
STAT5 and interleukin 7 (IL-7) signaling are thought to control B lymphopoiesis by regulating the expression of key transcription factors and by activating variable (V(H)) gene segments at the immunoglobulin heavy-chain (Igh) locus. Using conditional mutagenesis to delete the gene encoding the transcription factor STAT5, we demonstrate that the development of pro-B cells was restored by transgenic expression of the prosurvival protein Bcl-2, which compensated for loss of the antiapoptotic protein Mcl-1. Expression of the genes encoding the B cell-specification factor EBF1 and the B cell-commitment protein Pax5 as well as V(H) gene recombination were normal in STAT5- or IL-7 receptor alpha-chain (IL-7Ralpha)-deficient pro-B cells rescued by Bcl-2. STAT5-expressing pro-B cells contained little or no active chromatin at most V(H) genes. In contrast, rearrangements of the immunoglobulin-kappa light-chain locus (Igk) were more abundant in STAT5- or IL-7Ralpha-deficient pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and the developmental ordering of immunoglobulin gene rearrangements by suppressing premature Igk recombination in pro-B cells.
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Linfocitos B/citología , Diferenciación Celular/genética , Células Progenitoras Linfoides/citología , Linfopoyesis/genética , Factor de Transcripción STAT5/genética , Transducción de Señal/inmunología , Animales , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Regulación de la Expresión Génica/inmunología , Reordenamiento Génico/genética , Reordenamiento Génico/inmunología , Genes de Inmunoglobulinas/genética , Genes de Inmunoglobulinas/inmunología , Interleucina-7/genética , Interleucina-7/inmunología , Células Progenitoras Linfoides/inmunología , Linfopoyesis/inmunología , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5/inmunologíaRESUMEN
Primary immunodeficiencies (PIDs) are immune disorders resulting from defects in genes involved in immune regulation, and manifesting as an increased susceptibility to infections, autoimmunity, and cancer. However, the molecular basis of some prevalent entities remains poorly understood. Epigenetic control is essential for immune functions, and epigenetic alterations have been identified in different PIDs, including syndromes such as immunodeficiency-centromeric-instability-facial-anomalies, Kabuki, or Wolf-Hirschhorn, among others. Although the epigenetic changes may differ among these PIDs, the reversibility of epigenetic modifications suggests that they might become potential therapeutic targets. Here, we review recent mechanistic advances in our understanding of epigenetic alterations associated with certain PIDs, propose that a fully epigenetically driven mechanism might underlie some PIDs, and discuss the possible prophylactic and therapeutic implications.
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Epigénesis Genética/inmunología , Síndromes de Inmunodeficiencia/inmunología , Epigénesis Genética/genética , Humanos , Síndromes de Inmunodeficiencia/genéticaRESUMEN
Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the dimethylation of Histone 3 in Lysine 36 (H3K36me2). Until recently, it was considered as merely an intermediate towards the generation of the trimethylated form, but recent data support a more specific role in many aspects of genome regulation. H3K36 dimethylation is mainly carried out by proteins of the Nuclear SET Domain (NSD) family, among which NSD2 is one of the most relevant members with a key role in normal hematopoietic development. Consequently, NSD2 is frequently altered in several types of tumors-especially in hematological malignancies. Herein, we discuss the role of NSD2 in these pathological processes, and we review the most recent findings in the development of new compounds aimed against the oncogenic forms of this novel anticancer candidate.
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Enfermedades Hematológicas , Neoplasias , Epigénesis Genética , Enfermedades Hematológicas/genética , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Humanos , Lisina/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Represoras/genéticaRESUMEN
Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.
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Síndromes Mielodisplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Preleucemia , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Preleucemia/genética , Translocación GenéticaRESUMEN
"An International Meeting on Wolf-Hirschhorn Syndrome (WHS)" was held at The University Hospital La Paz in Madrid, Spain (October 13-14, 2017). One hundred and twenty-five people, including physicians, scientists and affected families, attended the meeting. Parent and patient advocates from the Spanish Association of WHS opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes. These proceedings will review the major points of discussion.
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Cromosomas Humanos Par 4/inmunología , Discapacidades del Desarrollo/genética , Convulsiones/genética , Síndrome de Wolf-Hirschhorn/genética , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/patología , Femenino , Humanos , Fenotipo , Convulsiones/epidemiología , Convulsiones/terapia , España/epidemiología , Síndrome de Wolf-Hirschhorn/epidemiología , Síndrome de Wolf-Hirschhorn/terapiaRESUMEN
Exposure to extremely low-frequency magnetic fields (ELF-MFs) has been classified by the International Agency for Research on Cancer (IARC) as "possibly carcinogenic to humans," based on limited scientific evidence concerning childhood leukemia. This assessment emphasized the lack of appropriate animal models recapitulating the natural history of this disease. Childhood B-cell acute lymphoblastic leukemia (B-ALL) is the result of complex interactions between genetic susceptibility and exposure to exogenous agents. The most common chromosomal alteration is the ETV6-RUNX1 fusion gene, which confers a low risk of developing the malignancy by originating a preleukemic clone requiring secondary hits for full-blown disease to appear. To develop potential prophylactic interventions, we need to identify the environmental triggers of the second hit. Recently, we generated a B-ALL mouse model of the human ETV6-RUNX1+ preleukemic state. Here, we present the results from the ARIMMORA pilot study, obtained by exposing 34 Sca1-ETV6-RUNX1 mice (vs. 27 unexposed) to a 50 Hz magnetic field of 1.5 mT with both fundamental and harmonic content, with an on/off cycle of 10 min/5 min, for 20 h/day, from conception until 3 months of age. Mice were monitored until 2 years of age and peripheral blood was periodically analyzed by flow cytometry. One of the exposed mice developed B-ALL while none of the non-exposed did. Although the results are statistically non-significant due to the limited number of mice used in this pilot experiment, overall, the results show that the newly developed Sca1-ETV6-RUNX1 mouse can be successfully used for ELF-MF exposure studies about the etiology of childhood B-ALL. Bioelectromagnetics. 2019;40:343-353. © 2019 Bioelectromagnetics Society.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Campos Electromagnéticos/efectos adversos , Leucemia Experimental , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogénicas c-ets/genética , Ondas de Radio/efectos adversos , Proteínas Represoras/genética , Animales , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Humanos , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Represoras/metabolismo , Proteína ETS de Variante de Translocación 6RESUMEN
Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype-phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions.
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Transformación Celular Neoplásica/genética , Estudios de Asociación Genética , Neoplasias/genética , Oncogenes/fisiología , Animales , Biología Celular , Proliferación Celular , Transformación Celular Neoplásica/patología , Inestabilidad Cromosómica , Humanos , Ratones , Modelos Biológicos , Mutación , Neoplasias/patología , Neoplasias/terapia , Células Madre Neoplásicas , Oncogenes/genéticaRESUMEN
The transcription factor E2A controls the initiation of B lymphopoiesis, which is arrested at the pre-pro-B cell stage in E2A-deficient mice. Here, we demonstrate by conditional mutagenesis that E2A is essential for the development of pro-B, pre-B, and immature B cells in the bone marrow. E2A is, however, dispensable for the generation of mature B cells and plasma cells in peripheral lymphoid organs. In contrast, germinal center B cell development is impaired in the absence of E2A despite normal AID expression and class-switch recombination. Molecular analysis revealed that E2A is required not only for initiating but also for maintaining the expression of Ebf1, Pax5, and the B cell gene program in pro-B cells. Notably, precocious Pax5 transcription from the Ikzf1 locus promotes pro-B cell development in E2A-deficient mice, demonstrating that ectopic Pax5 expression is sufficient to activate the B lymphoid transcription program in vivo in the absence of E2A.
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Linfocitos B/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Centro Germinal/inmunología , Factor de Transcripción Ikaros/metabolismo , Células Progenitoras Linfoides/citología , Linfopoyesis , Factor de Transcripción PAX5/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Células de la Médula Ósea/citología , Línea Celular , Supervivencia Celular , Centro Germinal/metabolismo , Factor de Transcripción Ikaros/genética , Células Progenitoras Linfoides/metabolismo , Linfopoyesis/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Mutagénesis , Factor de Transcripción PAX5/genética , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismoRESUMEN
Cellular plasticity is the capacity that cells have to change their fate and adopt a new identity. Plasticity is essential for normal development and for tissue regeneration and, in an experimental setting, for the induction of pluripotency. All these processes involve a reprogramming of the cellular identity, mediated by signals from the environment and/or by internal changes at the transcriptional and epigenetic levels. Tumorigenesis is a process in which normal cells acquire a new malignant identity and give rise to a clonal aberrant population. This is only possible if the initiating cell has the necessary plasticity to undergo such changes, and if the oncogenic event(s) initiating cancer has the essential reprogramming capacity so as to be able to lead a change in cellular identity. The molecular mechanisms underlying tumoral reprogramming are the pathological counterparts of the normal processes regulating developmental plasticity or experimentally-induced reprogramming. In this review we will first revise the main features of non-pathological examples of reprogramming, and then we will describe the parallelisms with tumoral reprogramming, and we will also delineate how the precise knowledge of the reprogramming mechanisms offers the potential for the development of new therapeutical interventions. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
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Desdiferenciación Celular/fisiología , Reprogramación Celular , Neoplasias/patología , Animales , Reprogramación Celular/genética , Crecimiento y Desarrollo/genética , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Neoplasias/genética , Células Madre Neoplásicas/fisiología , Regeneración/genéticaRESUMEN
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.
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Regulación Neoplásica de la Expresión Génica , Factor de Transcripción MafB/metabolismo , Mieloma Múltiple/metabolismo , Animales , Antígenos CD34/biosíntesis , Antígenos Ly/metabolismo , Linfocitos B/metabolismo , Metilación de ADN , ADN Complementario/metabolismo , Epigénesis Genética , Perfilación de la Expresión Génica , Biblioteca de Genes , Células Madre Hematopoyéticas/citología , Humanos , Hibridación Fluorescente in Situ , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Mieloma Múltiple/genética , Translocación GenéticaRESUMEN
We describe a method to correlate E-fields induced by exposure to extremely low frequency magnetic fields in laboratory mice and rats during in vivo experiments to those induced in children. Four different approaches of mapping relative dose rates between humans and rodents are herein proposed and analyzed. Based on these mapping methods and volume averaging guidelines published by the International Commission on Non-Ionizing Radiation Protection (ICNRP) in 2010, maximum and median induced field values for whole body and for tissues of children and rodents were evaluated and compared. Median induced electric fields in children younger than 10 years old are in the range 5.9-8.5 V/m per T (±0.4 dB). Maximum induced electric fields, generally in the skin, are between 48 V/m and 228 V/m per T (±4 dB). To achieve induced electric fields of comparable magnitude in rodents, external magnetic field must be increased by a factor of 4.0 (±2.6 dB) for rats and 7.4 (±1.8 dB) for mice. Meanwhile, to achieve comparable magnetic field dose in rodents, ratio is close to one. These induced field dose rates for children and rodents can be used to quantifiably compare experimental data from in vivo studies with data on exposure of children from epidemiological studies, such as for leukemia. Bioelectromagnetics. 37:310-322, 2016. © 2016 Wiley Periodicals, Inc.
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Campos Magnéticos , Radiometría/métodos , Animales , Niño , Preescolar , Simulación por Computador , Femenino , Humanos , Lactante , Masculino , Ratones , Ratas , Especificidad de la Especie , IncertidumbreRESUMEN
Exposure to extremely low-frequency magnetic fields (ELF-MF) was evaluated in an International Agency for Research on Cancer (IARC) Monographs as "possibly carcinogenic to humans" in 2001, based on increased childhood leukemia risk observed in epidemiological studies. We conducted a hazard assessment using available scientific evidence published before March 2015, with inclusion of new research findings from the Advanced Research on Interaction Mechanisms of electroMagnetic exposures with Organisms for Risk Assessment (ARIMMORA) project. The IARC Monograph evaluation scheme was applied to hazard identification. In ARIMMORA for the first time, a transgenic mouse model was used to mimic the most common childhood leukemia: new pathogenic mechanisms were indicated, but more data are needed to draw definitive conclusions. Although experiments in different animal strains showed exposure-related decreases of CD8+ T-cells, a role in carcinogenesis must be further established. No direct damage of DNA by exposure was observed. Overall in the literature, there is limited evidence of carcinogenicity in humans and inadequate evidence of carcinogenicity in experimental animals, with only weak supporting evidence from mechanistic studies. New exposure data from ARIMMORA confirmed that if the association is nevertheless causal, up to 2% of childhood leukemias in Europe, as previously estimated, may be attributable to ELF-MF. In summary, ARIMMORA concludes that the relationship between ELF-MF and childhood leukemia remains consistent with possible carcinogenicity in humans. While this scientific uncertainty is dissatisfactory for science and public health, new mechanistic insight from ARIMMORA experiments points to future research that could provide a step-change in future assessments. Bioelectromagnetics. 37:183-189, 2016. © 2016 Wiley Periodicals, Inc.
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Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.
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Caspasas/genética , Células Madre Hematopoyéticas/metabolismo , Linfoma/patología , Proteínas de Neoplasias/genética , Oncogenes , Animales , Humanos , Ratones , Ratones Transgénicos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B/metabolismo , Transcripción GenéticaRESUMEN
SUMMARY: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Niño , Humanos , Síndromes Mielodisplásicos/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Mutación de Línea Germinal , Leucemia Mieloide Aguda/genéticaRESUMEN
In human cancers, all cancerous cells carry the oncogenic genetic lesions. However, to elucidate whether cancer is a stem cell-driven tissue, we have developed a strategy to limit oncogene expression to the stem cell compartment in a transgenic mouse setting. Here, we focus on the effects of the BCR-ABLp210 oncogene, associated with chronic myeloid leukaemia (CML) in humans. We show that CML phenotype and biology can be established in mice by restricting BCR-ABLp210 expression to stem cell antigen 1 (Sca1)(+) cells. The course of the disease in Sca1-BCR-ABLp210 mice was not modified on STI571 treatment. However, BCR-ABLp210-induced CML is reversible through the unique elimination of the cancer stem cells (CSCs). Overall, our data show that oncogene expression in Sca1(+) cells is all that is required to fully reprogramme it, giving rise to a full-blown, oncogene-specified tumour with all its mature cellular diversity, and that elimination of the CSCs is enough to eradicate the whole tumour.
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Expresión Génica , Genes abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Células Madre , Animales , Ataxina-1 , Ataxinas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/análisis , Proteínas Nucleares/análisis , Análisis de SupervivenciaRESUMEN
Lineage commitment and differentiation to a mature cell type are considered to be unidirectional and irreversible processes under physiological conditions. The commitment of haematopoietic progenitors to the B-cell lineage and their development to mature B lymphocytes critically depend on the transcription factor encoded by the paired box gene 5 (Pax5). Here we show that conditional Pax5 deletion in mice allowed mature B cells from peripheral lymphoid organs to dedifferentiate in vivo back to early uncommitted progenitors in the bone marrow, which rescued T lymphopoiesis in the thymus of T-cell-deficient mice. These B-cell-derived T lymphocytes carried not only immunoglobulin heavy- and light-chain gene rearrangements but also participated as functional T cells in immune reactions. Mice lacking Pax5 in mature B cells also developed aggressive lymphomas, which were identified by their gene expression profile as progenitor cell tumours. Hence, the complete loss of Pax5 in late B cells could initiate lymphoma development and uncovered an extraordinary plasticity of mature peripheral B cells despite their advanced differentiation stage.