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Function of oncogenes in cancer development: a changing paradigm

2013; Springer Nature; Volume: 32; Issue: 11 Linguagem: Inglês

10.1038/emboj.2013.97

1460-2075

Carolina Vicente‐Dueñas, Isabel Romero-Camarero, César Cobaleda, Isidro Sánchez‐García,

Cancer-related Molecular Pathways

Review30 April 2013free access Function of oncogenes in cancer development: a changing paradigm Carolina Vicente-Dueñas Carolina Vicente-Dueñas Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Isabel Romero-Camarero Isabel Romero-Camarero Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Cesar Cobaleda Corresponding Author Cesar Cobaleda Centro de Biologia Molecular Severo Ochoa, CSIC/UAM, Nicolas Cabrera 1, Madrid, Spain Search for more papers by this author Isidro Sánchez-García Corresponding Author Isidro Sánchez-García Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Carolina Vicente-Dueñas Carolina Vicente-Dueñas Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Isabel Romero-Camarero Isabel Romero-Camarero Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Cesar Cobaleda Corresponding Author Cesar Cobaleda Centro de Biologia Molecular Severo Ochoa, CSIC/UAM, Nicolas Cabrera 1, Madrid, Spain Search for more papers by this author Isidro Sánchez-García Corresponding Author Isidro Sánchez-García Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain Search for more papers by this author Author Information Carolina Vicente-Dueñas1,2, Isabel Romero-Camarero1,2, Cesar Cobaleda 3 and Isidro Sánchez-García 1,2 1Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain 2Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain 3Centro de Biologia Molecular Severo Ochoa, CSIC/UAM, Nicolas Cabrera 1, Madrid, Spain *Corresponding authors. Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Tel.:+34 923238403; Fax:+34 923294813; E-mail: [email protected] de Biologia Molecular Severo Ochoa, CSIC/UAM, Nicolas Cabrera 1, Madrid 28049, Spain. Tel.:+34 911964692; Fax:+34 911964420; E-mail: [email protected] The EMBO Journal (2013)32:1502-1513https://doi.org/10.1038/emboj.2013.97 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info 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. Introduction For decades, contemporary cancer research has been mainly focused on the altered controls of proliferation in tumoural cells. This has been reflected in the therapeutic approaches employed in the clinic to treat the patients: with very few exceptions, anti-cancer treatments are targeted at the mechanisms of abnormal tumoural growth. These problems result in the eventual failure of therapy, that is often accompanied by the development of drug resistance and by metastatic dissemination. For this reason, an urgent goal of cancer research is to understand how to counteract the mechanisms that underlie the ability of normal cells to become cancer cells in the first place. The complexity of the properties of cancer cells was distilled by Hanahan and Weinberg (2011) into ‘nine essential alterations in cell physiology that collectively dictate malignant growth’. Cancer cells are the foundation of the disease: they initiate the tumours and drive cancer progression forward, and they are the ones carrying the oncogenic and tumour suppressor mutations that define cancer as a genetic disease (Hanahan and Weinberg, 2011). However, we still do not understand sufficiently well the underlying mechanisms leading to the origin of these cells, so as to have a sizable impact on cancer mortality (Jemal et al, 2009). As a result, our progress is incremental and largely empirical, leading only to slight improvements in treatments, surgical interventions or radiation regimes. These may provide some benefit, but they seem unable of bringing the disease itself to an end. Thus, a complete understanding of the cancer process requires a more detailed knowledge of the mechanisms giving rise to neoplastic growth, and is a prerequisite, not only for the understanding of the genesis of human cancer but also for the identification of the molecular events responsible for cancer maintenance. In spite of this, all the aspects related to the alterations of the normal developmental regulatory mechanisms in carcinogenesis have received comparatively little attention during the process leading to the definition of the hallmarks of cancer cells. But in fact, if cellular fate was immovable, cancer would not be possible, since no new lineages could be generated other than the normal, physiological ones. Here is where the mechanisms regulating tumour cellular identity play an essential role in allowing cancers to arise and hopefully, as we will discuss, they might be the key to its eradication. The aim of this review is to discuss the impact that oncogenes have in establishing the identity of the tumour cell, and how a better understanding of this previously unexplored mode of action of the oncogenes should lead us to a deeper knowledge of carcinogenesis, and to the development of new treatments. Cancer cells and oncogene addiction During the last four decades, scientific research has clearly demonstrated the relevance of oncogenes in human cancer. Since the discovery that human tumours contain activated oncogenes (Der et al, 1982; Goldfarb et al, 1982; Parada et al, 1982; Pulciani et al, 1982; Santos et al, 1982; Shih and Weinberg, 1982), many efforts have been made to understand their causal role in cancer development. All this work has shown that oncogene expression is not only required for cancer initiation but also for the maintenance of the disease, and has kept oncogenes in the limelight as the central anti-cancer therapeutic targets. When the oncogenic expression is driven by tissue-specific promoters in genetically engineered mouse models, tumours arise at high frequency, but they regress when the inducing stimulus is switched off (Chin et al, 1999; Huettner et al, 2000; Boxer et al, 2004), therefore suggesting that oncogenes are indeed the Achilles’ heel of cancers (Weinstein, 2002). This current model of cancer is in agreement with the fact that, in human cancers, all cancerous cells, with independence of the cellular heterogeneity existing within the tumour, carry the same initiating oncogenic genetic lesions. Overall, these observations seem to point towards an homogenous mode of action for oncogenes within cancer cells, since the brief inactivation of the different single tumour-inducing oncogenes can cause cancer remission in these model systems. Unfortunately however, the therapies based on this cancer model fail to eradicate tumours in humans (see below). These clinical observations suggest that, in human patients, oncogene-induced tumorigenesis might not be reversible through the unique inactivation of the gene defect(s) initiating cancer development. But then, what are the mechanisms of tumour relapse by which tumours evolve to escape oncogene dependence? These therapeutic failures cannot be explained just by invoking the existence of cancer stem cells (CSCs) or by the known cellular plasticity of tumours. Indeed, both aspects only imply that a tumoural population that is genetically homogeneous may nevertheless appear as phenotypically heterogeneous, due to the presence of cells in different states of differentiation (Hanahan and Weinberg, 2011). However, the aforementioned observations, derived from human targeted-therapy failure, might suggest that oncogenes have a mode of action that is not homogenous throughout the cancer cell population. This would explain the different sensitivity towards anti-oncogene-targeted therapies among the different cancer cellular stages. Recent in vivo genetic evidences have shown that human oncogenes are capable of reprogramming early stem/precursor cells towards specific differentiated tumour cell fates, but they are not required within the malignant cells. These results not only highlight a previously unrecognized role for human oncogenes but also provide evidence for a previously unmodeled process of tumorigenesis, in which the programming of the malignant phenotype has already taken place at the stem cell stage. Oncogene–target cell interaction In the last years, a new recognition of the role of aberrant differentiation at the root of cancer has arisen, mainly driven by the coming of age of the ‘cancer stem cell’ theory. From this point of view, a comprehensive knowledge of the developmental mechanisms by which normal target cells acquire their tumour identity is essential to understand cancer development. Cytogenetic and molecular genetic analyses have identified that many types of cancer are specifically associated with consistent defined genetic events (Mitelman et al, 2013). The expression of each one of these genetic lesions is associated almost exclusively with a characteristic subgroup of human cancer (Figure 1). Not only are these genetic lesions of clinical importance, as they may serve as unequivocal diagnostic markers, but they also provide important clues to the understanding of the cellular mechanisms behind cancer development. However, these genotype–phenotype correlations established in humans have demanded during the last three decades that we explain the nature of this intimate association between each genetic lesion and the phenotype (particular type of cancer) with which it is associated. Two different hypotheses have been considered to explain this link (Figure 2). In the classical view of the initiation and progression of cancer, the initiating genetic alteration takes place and is required for the immortalization of a committed/differentiated target cell (Figure 2A). Such cell will afterwards acquire additional genetics hits over time. The acquisition of additional hits aggravates the deregulation of the behaviour of the differentiated target cell, therefore leading to the clinically recognized features of cancers. This is the model that has traditionally been assumed in the study of oncogenesis, taking for granted that the phenotype of the tumour cells was a reflection of that of the normal cell that gave rise to the tumour in the first place. Since the beginning, there were already some classical examples in which this was clearly not the case, for example, chronic myelogenous leukaemia (CML), where Fialkow et al (1977) first suggested nearly 40 years ago that the disease arose from rare transformed hematopoietic stem cells (HSCs), since the t(9;22) chromosomal translocation could be found in most types of differentiated haematopoietic cells. But, in most cases, cancerous cells do share similarities with some non-pathological differentiated cell types. Therefore, for every kind of cancer, the cell-of-origin was assumed to be the corresponding normal differentiated cell. Figure 1.Examples of cancer types generated directly from mouse stem/progenitor cells by tumour fate reprogramming. Human cancer is associated to specific and consistent genetic events. Each one of these genetic defects is observed exclusively in characteristic subgroups of human cancer. In mouse models, as illustrated, specific genotype alterations associated to human cancer (medium circle) give rise to specific phenotypes (outer circle) when targeted to the stem cell/progenitor compartment (see text for details). Download figure Download PowerPoint Figure 2.Proposed model for the role of human cancer gene defects in tumour cell fate specification. (A) Traditionally, the human cancer genetic defects have been thought to act on cells already committed to a differentiation program, in such a way that the tumoural phenotype is derived from that of the initial differentiated target cell. (B) Alternatively, the latest findings support a view in which the oncogenic lesion acts on stem/progenitor cells by imposing a given, oncogene-specific, tumour-differentiated cell fate. Download figure Download PowerPoint The other way of interpreting the genotype–phenotype correlations observed between genetic lesions and a given tumoural type is to consider the possibility that the oncogene is directly responsible of imposing the specific characteristics of the tumour phenotype (Figure 2B). This is in fact what happens in CML, where the oncogene is expressed at the stem cells but the phenotype manifests as a granulocytic expansion. Cancer stem cell theory The CSC hypothesis is in good agreement with the interpretation of oncogenesis presented in Figure 2B (Reya et al, 2001; Sanchez-Garcia et al, 2007). The term tumour/CSC (or cancer-maintaining cell, see the definition of terms in Figure 3) was first coined nearly 40 years ago to explain the observation that only a small subset of multiple myeloma cells were capable of clonogenic growth (Hamburger and Salmon, 1977a; Hamburger and Salmon, 1977b), and it was demonstrated experimentally for the first time for a human cancer by Bonnet and Dick (1997). The CSC theory proposes that tumours are stem cell-based tissues, like any other one in the organism. This implies the existence of a hierarchical structure within the tumour and, most importantly, that not all the cells forming the tumoural mass are equally competent for regenerating the tumour, and that the phenotype of the tumoural cells is, to a large degree, genetically programmed by the oncogene from the tumour stem cell stage. This would imply that, both in the cases of tumour regeneration after transplantation, and of tumour relapse after therapy, only a certain tumoural subpopulation (the cells possessing stem properties) is responsible for the cancer recurrence. The existence of CSCs is the reason why current therapies are incapable, in most cases, of eradicating the disease, as these cells are, in general, resistant to antiproliferative therapies and no other options are available due to toxicities to sensitive normal stem cells. Indeed, in the same way that normal stem cells continue giving rise to normal tissues after chemotherapy (regrowth of lost hair, regeneration of the hematopoietic compartments, reparation of intestinal mucosae), CSCs regenerate the tumour as well. There are a few exceptions to this rule, such as testicular carcinoma, where tumour stem cells are more sensitive to the chemotherapy cocktail than normal stem cells, and then cancer can be cured. There are discrepancies among researchers and, most probably, big differences among different cancer types, in the calculated proportions of CSCs within a tumour, ranging from very few to a large 25% (Quintana et al, 2008; Cobaleda and Sanchez-Garcia, 2009; Vicente-Duenas et al, 2009a; Vicente-Duenas et al, 2009b). Nevertheless, independently of this fact, the most relevant aspect is that not all the cells composing the tumour mass possess the capacity of regenerating it. The question that follows is then: nowadays, it is accepted that the tumour mass comes from the cancer stem cells but, where do they come from themselves? What is their origin? Figure 3.Developmental biology of cancer cells. (A) Cancer cell-of-origin (or cancer-initiating cell): the cell where the first genetic lesion linked to the development of the tumour takes place. It might be located anywhere within the physiological differentiation pathway. It does not need to have any phenotypic relationship with the final phenotype of the tumour cells (either stem or differentiated). (B) CSC (cancer-maintaining cell): those cells that have the capacity to regenerate all the cellular diversity of the tumour. They retain broad self-renewal potential and differentiation potential. They arise initially from the cancer cell-of-origin, and then they can self-propagate. (C) Tumoural reprogramming: the process by which the initial oncogenic lesion(s) can ‘reset’ the epigenetic and/or transcriptome status of an initially healthy cell (the cancer cell-of-origin), therefore establishing a new, pathological differentiation program ultimately leading to cancer development, where the oncogenic lesion(s) does not need to be present anymore once the initial cancer fate-inducing change has taken place. Download figure Download PowerPoint The nature of the cancer cell-of-origin This cancer cell-of-origin (or cancer-initiating cell, not to be confused with the CSCs which, as we have explained, are the cancer-maintaining cells of a tumour that is already developed) is the, initially, healthy cell (it doesn't necessarily have to be a stem cell) that will be reprogrammed by the oncogenic hit(s) and will finally give rise to a (pre)tumoural cell with stem cell properties (Figure 3A). From a developmental point of view, there are two possibilities to be considered in this context. One option is that the cell-of-origin that suffers the first oncogenic hit(s) is a stem cell: in this case, a new tumoural stem cell will be reprogrammed to generate the new pathological tissue instead of the normal one. In the case of CML, by restricting the expression of the oncogenic alteration to the stem cell/progenitor compartment in genetically modified mice, it has been possible to generate a tumour very similar to the human one, with its cellular variability (Perez-Caro et al, 2009; Vicente-Duenas et al, 2009b). In the case of intestinal cancers, when the oncogenic hit (activation of the Wnt signalling pathway) is directed to the stem cell compartment in mouse models, intestinal adenomas are generated that maintain their internal developmental hierarchy; however, when the targeting of the oncogenic hits is directed to differentiated intestinal epithelial cells, only short-lived, small microadenomas appear (Barker, 2008; Barker et al, 2009; Zhu et al, 2009). These data strongly suggest that the tumour must have its origin in the crypt stem cells. Something similar happens in the context of tumours of the nervous system; when oncogenic lesions associated to astrocytomas are targeted to tissue progenitors (the subventricular zone), tumours originate, while only astrogliosis happens when the targeted cells are differentiated adult parenchymal cells (Alcantara Llaguno et al, 2009). These examples and others (Dirks, 2008; Joseph et al, 2008; Zheng et al, 2008) prove that the initiating event can take place in a normal stem cell, even if the mature tumour is composed by differentiated cells, and that the oncogenic lesions possess reprogramming capacity, leading to the appearance of a mature tumoural differentiated population (Vicente-Duenas et al, 2009b). There is, however, other option regarding the nature of the cancer cell-of-origin: it might happen that a differentiated cell is the original target of the initiating oncogenic hit(s), and in the subsequent process of oncogene-mediated tumoural reprogramming, it regains stem cell characteristics to become a true CSC. This possibility has, however, two prerequisites: on the cell side, it implies that, even though it is a differentiated cell, it must possess enough plasticity so as to be reprogrammable (at least, by this specific oncogene). On the oncogene side, the alteration must be able of activating the required programs to finally confer stem cell properties (at least, for this specific target cell). It has been demonstrated that some oncogenes can generate CSCs when they are introduced into committed target cells; this is the case for MOZ-TIF2 (Huntly et al, 2004), MLL-AF9 (Krivtsov et al, 2006; Somervaille and Cleary, 2006), MLL-ENL (Cozzio et al, 2003), MLL-GAS (So et al, 2003) or PML-RARa (Guibal et al, 2009; Wojiski et al, 2009). MLL-AF9, for example, can confer the property of self-renewal to committed granulocyte–macrophage progenitors, by activating in them a stem cell-like program (Krivtsov et al, 2006). Similarly, c-Myc can originate epithelial CSCs by inducing an embryonic stem cell-like transcriptional program in differentiated epithelial cells (Wong et al, 2008). However, other oncogenes are unable of conferring self-renewal properties, like in the case of BCR-ABLp190 (Huntly et al, 2004). In these cases, where the oncogene cannot confer stem cell properties, it might however originate a pre-cancerous cell that can afterwards, with the accumulation of additional alterations leading to the acquisition of stem cell properties, give finally rise to a CSC (Chen et al, 2007). For example, it has recently been described in intestinal tumorigenesis that the inflammatory tumour microenvironment can, through elevated NF-κB signalling, lead to an enhanced Wnt activation that, in turn, causes dedifferentiation of non-stem cells and acquisition of tumour-initiating capacity (Schwitalla et al, 2013). In human gliomas, MEF promotes the acquisition of stem cell characteristics by upregulating Sox2 (Bazzoli et al, 2012), and other studies also suggest that gliomas can originate by dedifferentiation of neurons and astrocytes (Friedmann-Morvinski et al, 2012). This reprogramming effect of oncogenes does not have to be restricted to cells of the same lineage; for example, adipocyte-restricted activation of Sonic hedgehog signalling in mice gives rise to aggressive rhabdomyosarcomas, indicating that adipocyte progenitors can be the cell-of-origin of these tumours, that can therefore originate from non-skeletal muscle precursors (Hatley et al, 2012). In the initiation of basal carcinoma, constitutively active expression of an Smoothened mutant (SmoM2) in the adult epidermis leads to the appearance of tumour-initiating cells with the characteristics of embryonic hair follicle progenitors, caused by the reprogramming of adult interfollicular tumour-initiating cells (Youssef et al, 2012). Many of these aspects can be recapitulated, to a certain degree, in vitro, where CSC-like cells can be generated by oncogenic reprogramming of human somatic cells during neoplastic transformation (Scaffidi and Misteli, 2011). Indeed, human differentiated cells can be transformed in vitro by the action of telomerase, an oncogenic H-RasV12 mutant and the concomitant inhibition of p53 and pRB; during in vitro transformation, a subset of the fibroblasts are reprogrammed to a more primitive, multipotent cell type, possessing CSC characteristics and generating hierarchically organized tumours (Scaffidi and Misteli, 2011). The tumoural stem cell reprogramming hypothesis Cellular reprogramming refers to ‘the concept of rewiring the epigenetic and transcriptional network of one cell state to that of a different cell type’ (Hanna et al, 2008). When this process is induced by molecularly defined means it is called direct reprogramming. The term ‘reprogramming’ is very frequently used as it was restricted to direct reprogramming to induced pluripotent stem cells (iPSCs) by means of a specific cocktail of transcription factors (Takahashi and Yamanaka 2006; Takahashi et al, 2007). However, as defined above, ‘reprogramming’ also encompasses other processes of cell fate change, not necessarily involving the four Yamanaka transcription factors, and not always implying the existence of iPSCs as an end point (Figure 4). Accordingly, tumoural reprogramming is the process by which an oncogene (or cancer genetic alteration) can ‘reset’ the epigenetic and/or transcriptome status of an initially healthy cell (the cancer cell-of-origin), therefore establishing a new, pathological differentiation program ultimately leading to cancer development (Figures 3C and 4). Therefore, the parallelism with reprogramming to pluripotency is clear, (Krizhanovsky and Lowe, 2009; Perez-Caro et al, 2009). The existence of this process is, however, difficult to demonstrate in human cancers, since the initiating oncogenic lesions that reprogram the fate of the tumour-target cells are genetically preserved in the cancer-maintaining cells, and also throughout the different pathological cellular intermediates, until the final tumour differentiated cells, thus making it difficult to ascertain their molecular role at the different stages of tumour biology. Figure 4.Tumour stem cell reprogramming versus reprogramming to pluripotency. (A) Recent in vivo genetic evidences have shown that human oncogenes are capable of reprogramming early stem/precursor cells towards specific differentiated tumour cell fates, but they are not required afterwards, within the malignant cells. (B) ‘Hit-and-run’ reprogramming has grounding in other contexts outside of cancer, such as during induced pluripotent stem (iPS) cell formation in vitro. However, unlike the tumour stem cell reprogramming, the iPS process initiates in a differentiated cell (see text for details). Download figure Download PowerPoint One important conceptual and biological aspect of the molecular mechanisms of reprogramming to pluripotency is the fact that, once the way to pluripotency has been opened and the reprogramming per se has taken place, the pluripotent condition does not require the inducing factors anymore for its maintenance (Papp and Plath, 2013). Therefore, by parallelism, if CSCs are generated by a (tumoural) reprogramming process, then maybe the oncogenes that initiate tumour formation might not be required for tumour progression (Krizhanovsky and Lowe, 2009; Perez-Caro et al, 2009). This would explain the cases in which a pre-cancerous lesion exists stably as the single aberration in an abnormal cell population that will only progress to an open tumour when secondary hits occur. The initiating lesion would be the driving force in the reprogramming process, essential for tumorigenesis. However, once reprogramming has taken place, this initiating hit would only be a passenger mutation within the CSC, either without a significant function anymore, or even performing a different role, unrelated to the reprogramming one, in tumour expansion or proliferation. This mode of action would explain why well-designed targeted therapies fail in eradicating the disease, in spite of their apparent efficacy against the main tumour mass (see below). In vivo experimental model of tumoural stem cell reprogramming To be able to demonstrate this lack of homogeneity in the mode of actions of oncogenes throughout the biological history of the tumour, it would be necessary to dissect and isolate the function that the oncogene is playing at the earliest stages of the disease, at the level of the cell-of-origin. Indeed, to prove that the maintenance of the expression of the oncogene is not necessary for tumour progression beyond the initial step of reprogramming, one would need to find a way of restricting the expression of the oncogene to the stem/progenitor compartment. Such a system would also allow us to prove, if this was indeed the case, that the oncogenes that initiate tumour formation might be dispensable for tumour progression and/or maintenance. To shed light on this issue and to elucidate if cancer is a stem cell-driven tissue, we have used the locus control region of the mouse Sca1 (Ly6E.1) gene to restrict the expression of selected, specific human cancer-associated oncogenes to the stem cell compartment in a transgenic mouse setting (Perez-Caro et al, 2009; Vicente-Duenas et al, 2012a; Vicente-Duenas et al, 2012c; Romero-Camarero et al, 2013). We initially focused our studies on BCR-ABLp210+ CML, since this is widely accepted to be