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Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by hit-and-run oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a hit-and-run role in lymphomagenesis. © 2014 Macmillan Publishers Limited. All rights reserved.

El cáncer es un término genérico que designa un amplio grupo de enfermedades que pueden afectar a cualquier parte del organismo. En el año 2012, se cobró la vida de 8.000.000 personas, y es que, a pesar de todos los esfuerzos realizados a conocer la biología del cáncer, la supervivencia global no se ha visto incrementada de manera notoria y, en la mayoría de los casos se debe a una detección precoz de la enfermedad. Nuestro grupo de investigación está interesado en estudiar las etapas iniciales del cáncer, que van a convertir una célula pretumoral en una célula madre cancerígena. Una célula madre cancerígena es una célula neoplásica con características de célula madre, esto es, autorrenovación y capacidad de diferenciación, capaz de regenerar toda la diversidad celular presente en el tumor. La existencia de las células madre cancerígenas explicaría por qué algunos pacientes, tras un período de remisión inicial, sufren recaídas. Estas células madre cancerígenas serían las responsables de regenerar toda la masa tumoral de células. Sin embargo, no debemos confundir la célula madre cancerígena con la célula origen del cáncer, que es la célula donde va a tener lugar el primer evento oncogénico. En este contexto debemos hablar de la reprogramación tumoral, que es el proceso por el cual un evento oncogénico reprogramaría una célula, en este caso la célula origen del cáncer mediante alteraciones epigenéticas en su transcriptoma, estableciendo en ella un programa de diferenciación patológico que culminaría en el desarrollo de una masa tumoral, donde el oncogén ya no sería necesario ni para la progresión ni para el mantenimiento del cáncer. Nosotros quisimos estudiar la reprogramación tumoral en el contexto del linfoma difuso de células B grandes mediante la sobreexpresión de HGAL y en la génesis de leucemias linfoblásticas T tras la sobreexpresión de Lmo2.

After many years of struggle against the traditional theories, cancer stem cells (CSCs) are finally coming of age as the main responsible for the maintenance and relapse of human cancer. there are two main reasons for this fact. First, the enormous amount of quickly accumulating experimental evidences proving their existence and their contribution to cancer maintenance and survival in humans. Second, the patent e vidence of the very slow advance of our fight against cancer in the las 50 years. Indeed, althought early detection and screening programs have increased the chances of diagnosing cancer at very early stages, the prognosis for disseminated tumors is as dismal today as it was 5 decades ago. It is therefore clear that a new conceptual framework is required in our approach to treat cancer. The acknowledgement of the existence of CSCs provides this framework and opens new avenues for exploring therapeutic approaches. In this chapter we revise the most recent discoveries in the research aimed at the targeting and elimination of CSCs.

[Background]: Melanoma is responsible for almost 80% of the deaths attributed to skin cancer. Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. [Objectives]: We hypothesized that the phenotypic heterogeneity of human cutaneous melanomas is related to their content of CD133+ cells. [Methods]: We compared the percentages of CD133+ cells in 29 tumours from four classic types of melanoma: lentigo maligna melanoma (LMM), superficial spreading melanoma, nodular melanoma and acral lentiginous melanoma (ALM). Also, we compared the percentages of CD133+ cells in melanomas with different degrees of exposure to ultraviolet radiation: 16 melanomas from skin with chronic sun-induced damage and 13 melanomas from skin without such damage. [Results]: We found a statistically significant increase of CD133+ cells in three different contexts: in melanomas arising on skin with signs of chronic sun-induced damage vs. nonexposed skin, in melanomas in situ vs. invasive melanomas, and in LMM vs. ALM. The proportions of CD133+ cells did not differ among samples of normal skin with different degrees of sun exposure. A distinct subpopulation of CD133+CXCR4+ cancer stem cells (CSCs) was identified and shown to be related to the invasive phenotype of the tumours. [Conclusions]: Here, we provide evidence showing, for the first time, that an increase in the CD133+ cell content is associated both with melanomas arising on skin with signs of chronic sun-induced damage and in melanomas in situ with better prognosis. Moreover, our study further confirms the existence of a subpopulation of CD133+CXCR4+ CSCs in cutaneous melanomas with invasive phenotype and poor prognosis. What's already known about this topic? Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. What does this study add? In the present study, we provide evidence showing, fo

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.

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. © 2013 European Molecular Biology Organization.

Cancer stem cells (CSCs) are the pathological counterpart of normal somatic tissue stem cells. They possess the capacities to self-renew and to generate a more differentiated, rapidly dividing and expanding tumour progeny. Although they constitute just a small percentage of the tumour mass, they are responsible for its maintenance and, therefore, they should be the target of anticancer treatments. The existence of CSCs is still a matter of controversy for certain tumour types – some of which are actually frequent and clinically relevant – but it is confirmed in many others. Moreover, CSCs are predictably genetically diverse, and their frequency and phenotype can vary in the course of the disease. However, CSCs have nowadays been identified in almost all the frequent types of tumours, and recent findings have shown that CSC gene expression signatures can be predictive of adverse clinical outcome, therefore maintaining the study of CSCs at the forefront of cancer research.

The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. However, BCR-ABL was expressed and active in telomerase heterozygous and null leukemic hematopoietic stem cells. These results demonstrate that telomerase is essential for oncogene-induced reprogramming of hematopoietic stem cells in CML development and validate telomerase and the genes it regulates as targets for therapy in CML.

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.

Cancer is the subject of intense research around the world, but many questions about how the disease works remain unanswered. How exactly does cancer start and how do tumours grow? In fact, at present there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents are predicted to show clinical benefit in only small subpopulations of patients. The cancer stem cell model could explain not only how some cancers work but also why patients suffer relapses, providing a good opportunity to gain insight into the reasons why agents work or, more commonly, don't work, before going into a clinical trial.

LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis. © 2012 by The American Society of Hematology.

The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidences supporting these new points of view. Furthermore, in the case of B-cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research, and discuss their interrelationships and their implications for our understanding of the biology of the disease. © 2011 Landes Bioscience.