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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. This contribution introduces a new perspective on oncogenic transformation: certain oncogenes may act as ‘passengers’ to reprogram tissue‐specific stem/progenitor cell into a malignant cancer stem cell state.

The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5 +/− B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5 +/− Myd88 +/− mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5 +/− mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children. Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.

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. Infection or chronic inflammation is a risk factor for childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors show that the DNA editing enzyme AID is expressed in infected B cells but using genetic mouse models show that it does not contribute to leukemia pathogenesis.

B cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer. Although treatment has advanced remarkably in the past 50 years, it still fails in ~20% of patients. Recent studies revealed that more than 5% of healthy newborns carry preleukaemic clones that originate in utero, but only a small percentage of these carriers will progress to overt B-ALL. The drivers of progression are unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. Emerging evidence shows that a major driver for the conversion from the preleukaemic state to the B-ALL state is exposure to immune stressors, such as infection. Here, we discuss our current understanding of the environmental triggers and genetic predispositions that may lead to B-ALL, highlighting lessons from epidemiology, the clinic and animal models, and identifying priority areas for future research.Although many healthy newborns carry preleukaemic clones, only a small minority of infants will develop overt B cell acute lymphoblastic leukaemia. Here, the authors explore the idea that infections can serve as immune stressors that drive the progression of B cell acute lymphoblastic leukaemia.

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. Diffuse large B-cell lymphoma is an aggressive heterogeneous tumour type with poorly understood aetiology. Here, Green et al. show that transient expression of Bcl6 in haematopoietic stem cells is sufficient to induce mature B-cell lymphoma, indicating that it acts as a ‘hit-and-run’ oncogene.

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. Transgenic expression of the MafB oncogene in haematopoietic stem/progenitor cells induces plasma cell neoplasia reminiscent of human multiple myeloma and suggests DNA methylation as cause of malignant transformation.

B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

Ubiquitous expression of a resident K-Ras ᴳ¹²ⱽ oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras ᴳ¹²ⱽ expression only induced overt tumors in lungs. To identify these transformation-permissive cells, we induced K-Ras ᴳ¹²ⱽ expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras ᴳ¹²ⱽ oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC ⁺ alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras ᴳ¹²ⱽ expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10 ⁺ Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC ⁺ ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras ᴳ¹²ⱽ–driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC ⁺ ATII lesions. Finally, activation of K-Ras ᴳ¹²ⱽ during embryonic development under the control of a Sca1 promoter yielded CC10 ⁺, but not SPC ⁺, hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC ⁺ ATII cells were able to yield malignant adenocarcinomas.

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.

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,CREBBPmutations 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.CREBBPmutant 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 implicateCREBBPmutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.