Upstream eventMLL translocation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibitor binding to topoisomerase II leading to infant leukaemia||adjacent||High||Not Specified|
Life Stage Applicability
|Birth to < 1 month||High|
Key Event Relationship Description
Propagation of a leukaemic cell clone is based on both blockage of differentiation to more mature cells and ability to expand in an uncontrolled way. Formation of the MLL-rearranged fusion genes and their protein products are intimately involved in both the blocked differentiation of HSPCs and the expansion of the fusion gene-carrying clone. It is believed that the fusion gene product block cell differentiation by inhibiting the normal transcriptional programs and recruiting repressor molecules such as histone deacetylase enzymes (Greaves 2002; Teitell and Pandolfi 2009). Furthermore, the fusion gene product activates other key target genes, which ultimately lead to the propagation of transformed cell lines without normal restrictions (Greaves 2015; Sanjuan-Pla et al 2015). Therefore, the potential of both differentiation blockage and clonal expansion are inherent properties of the MLL-rearranged fusion product, based on the preservation of some original functions, even if in a modified form, and on the gain of some other functions due to the sequences from the new fusion partner gene (Marschalek 2010; Sanjuan-Pla et al 2015).
In principle all MLL fusion genes are potential initiating drivers, although clinical studies have shown a preponderance with infant leukaemia for only a few of these rearrangements. For infants diagnosed with ALL, approximately 60-80% carry an MLL rearrangement (Sam et al 2012; Jansen et al 2007), with predominant fusion partners being AF4 (41%), ENL (18%), AF9 (11%) or another partner gene (10%). In particular, the fusion gene MLL-AF4 shows a specific and consistent relationship with the disease (Menendez et al., 2009): however, it has been difficult to reproduce a manifest disease resulting from this rearrangement in in vivo animal models. For AML, about 30 % of the patients carry an MLL rearrangement.
The occurrence of MLL rearrangements at a very early fetal development is highly probable on the basis of neonatal blood spot analysis and by the high concordance rate of infant leukaemia in monozygotic twins (Ford et al 1993; Gale et al 1997; Sanjuan-Pla 2015). Menendez et al (2009) showed that MLL-AF4 fusion gene is present in bone marrow mesenchymal stem cells in infant leukaemia patients, but not in patients of childhood leukaemia, suggesting that the origin of the fusion gene is probably prehaematopoietic. Consequently, the affected cell, the so called leukaemia-initiating cell, may be an early prehaematopoietic mesodermal precursor, a hematopoietic stem cell or hematopoietic progenitor cell residing mainly in the liver (Greaves 2015; Sanjuan-Pla et al 2015).
MLL translocation sites (breakpoint sequences) in the therapy-related leukaemia fall within a few base pairs of etoposide-induced enzyme-mediated DNA cleavage site. Although rearrangements associated with infant leukaemias are often more complex than those observed in treatment-related leukaemias, many are nevertheless associated with stable TopoII-mediated DNA cut sites. Although all these findings are indirect regarding infant leukaemia, they are nevertheless rather persuasive in this respect.
Growing scientific evidence, including the stable genome of the patients, suggests that infant leukaemia originates from one “big-hit” occurring during a critical developmental window of stem cell vulnerability (Andersson et al 2013; Greaves 2015). Therefore, the totality of evidence suggests the essential role of the formation of MLL-AF4 (and other partner) fusion gene and product in causing pleiotropic effects in the affected cell and directing it to the obligatory pathway to the adverse outcome of leukaemia.
The MLL is the most common translocation gene in infant leukaemia. The N-terminal part of MLL becomes fused in frame to one of a large number of fusion partners, but in most cases, this fusion occurs between the N-terminal MLL and either AF4, AF6, AF9, AF10, or ENL (Krivtsov and Armstrong 2007). Due to the DNA-binding properties of the N-terminal MLL motif, these fusion proteins are always nuclear and bind to target genes controlled by MLL irrespective of the normal location of the C-terminal partner.
Many fusion proteins have been shown to recruit disruptor of telomeric silencing 1-like (DOT1L or officially KMT4, a histone methyltransferase that methylates lysine 79 located within the globular domain of histone H3, H3K79) to the promoters of MLL target genes. This recruitment seems to be a common feature of many oncogenic MLL fusion proteins (Chen and Armstrong, 2015). Although DOT1L is not genetically altered in the disease per se, its mislocated enzymatic activity is a direct consequence of the chromosomal translocation. Thus, DOT1L has been proposed to be a catalytic driver of leukemogenesis (Chen and Armstrong 2015). The enzymatic activity of DOT1L is critical to the pathogenesis of MLL, because methyltransferase-deficient Dot1L is capable of suppressing growth of MLL-rearranged cells. A small-molecule inhibitor of DOT1L inhibits cellular H3K79 methylation, blocks leukemogenic gene expression, and selectively kills cultured cells bearing MLL translocations (Chen and Armstrong 2015). One of the target gene of DOT1L is BCL-2, belonging to a family of anti-apoptotic genes, which maintains the survival of the MLL-rearranged cells (Benito et al 2015). Expression of BCL-2 is high in human MLL-AF4 leukemia cells from a large number of patients. A specific BCL-2 inhibitor, ABT-199 is capable of killing MLL-AF4 leukaemia cells and prevents cell proliferation in xenograft mouse leukaemia models (Benito et al 2015). Furthermore, a MLL-AF4 cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. The figure below provides a schematic representation of the molecular pathway.
MLL-rearranged acute lymphoblestic leukemisa activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2 specific antagonist ABT-199 (benito et al, Cell Rep 2015).
Possible facilitating mutated genes
Recurrent activating mutations in the components of the PI3K-RAS signalling pathway have been detected in almost half of the tested MLL-rearranged ALLs in one study (Andersson et al 2015). Prenatal origin of RAS mutations have been demonstrated also in other studies of infant leukaemia with frequencies of about 15-25 % of cases (Driessen et al 2013; Prelle et al 2013; Emerenciano et al 2015). Emerenciano et al (2015) are of the opinion that RAS mutations seem not to be driver mutations, but may aid disease onset by accelerating the initial expansion of cells.
Overall the activation of the RAS pathway could support the extremely rapid progression of the infant leukaemia. Under this view the mechanism may represent a factor modulating (i.e., increasing) the progression and severity of the adverse outcome, rather than a necessary key event (second hit) for infant leukaemia. In the transgenic MLL-AF4 mouse model, activated K-RAS accelerated disease onset with a short latency (Tamai et al 2011), possibly by augmenting the upregulation of HoxA9. In a recent study of Prieto et al (2016),the activated K-RAS enhanced extramedullary haematopoiesis of MLL-AF4 expressing cell lines and cord blood-derived CD34+ hematopoietic stem/progenitor cells that was associated with leucocytosis and central nervous system infiltration, both hallmarks of infant MLL-AF4 leukaemia. However, K-RAS activation was insufficient to initiate leukaemia, supporting that the involvement of RAS pathway is an important modifying factor in infant leukemia. It has also been demonstrated that MLL-AF6 fusion product sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukaemia cells and it is possible to attenuate the activation by tipifarnib, a RAS inhibitor (Manara et al 2014).
A possibility that MLL fusions render cells susceptible to additional chromosomal damage upon exposure to etoposide was studied by introducing MLL-AF4 and AF4-MLL via CRISPR/Cas9-genome editing in HEK293 cells as a model to study MLL fusion-mediated DNA-DSB formation/repair (Castano et al 2016). In short, the expression of fusion genes does neither influence DNA signaling nor DNA-DSB repair.
Evidence Supporting this KER
The overall scientific evidence, including the stable genome of patients, suggests that infant leukaemia originates from one “big-hit” occurring during a critical developmental window of stem cell vulnerability (Andersson et al 2013; Greaves 2015). Different from the “two-hit” model of the adult leukemias, the infant leukemia is a developmental disorder where the clonal expansion is a direct consequence of in utero MLL translocation.
There are animal models for infant leukaemia which recapitulate at least some salient aspects of the disease (Sanjuan-Pla et al 2015). However, for example the MLL-AF4 knock-in mice develop leukaemia only after a prolonged latency (Chen et al 2006), thus not recapitulating the ‘pathognomonic’ feature of infant leukaemia.
The biological plausibility linking the MLL translocation to infant leukaemia is strong. Rearrangement in the MLL gene is commonly associated with infant acute leukaemia and the disease has unique clinical and biological feature (Ernest et al. 2002). An in utero initiation, an extremely rapid progression, and a silent mutational landscape of infant leukaemia suggest that the MLL-translocation-associated gene fusion product is itself sufficient to spawn leukaemia and no “second hit” is required. Therapy-related leukaemias following exposure to the topo II poisons such as etoposide are characterized by the MLL chromosomal translocation (Libura et al. 2006, Super et al.1993) and translocations involving MLL are associated with a gain of function and leukemogenic effect (Yu et al. 1998). A critical developmentally early window of stem cell vulnerability, involving perhaps lesions based on epigenetically controlled regulatory factors, has been suggested to explain a rare occurrence and an exceptionally short latency of infant leukaemia (Greaves 2015; Sanjuan-Pla et al 2015). In primary HSPCs genome engineered for patient specific MLL translocations it was possible to show that this specific ‘artificial’ initiation can induce a selective advantage in survival in extended culturing and a higher clonogenic potential in colony forming assay (Breese et al. 2015).
Etoposide can induce the formation of a fusion gene as a result of a chromosomal translocation involving the mixed-lineage leukaemia (MLL) gene and other partner genes through topoisomerase II (topo II) “poisoning”.
Secondary acute leukaemia carrying MLL-r is an adverse effect observed in patients treated with etoposide . Characteristics of the disease are in many ways analogous to those in infant leukaemia (Joannides et al., 2010, 2011). This so-called therapy-associated acute leukaemia (t-AL) in adults is characterised by its short latency, <2 years between the treatment of the primary malignancy with epipodophyllotoxins and the clinical diagnosis of the secondary disease, and by the poor prognosis (Cowell and Austin, 2012; Ezoe, 2012; Pendleton et al., 2014). It is recognised that the MLL-r fusion genes are caused by etoposide because MLL-r have not been detected in bone marrow samples banked before the initiation of the treatment for the first malignancy (Cowell and Austin, 2012; Pendleton et al., 2014). Overall, the evidence supporting the causal relationship between etoposide-induced topo II inhibition and further formation of cleavage complexes leading to MLL-r is strong and could be regarded as ‘beyond reasonable doubt’. Also, the breakpoints in MLL or partner genes fall within a few base pairs of a drug-induced enzyme-mediated DNA cleavage site (Cowell and Austin, 2012, Pendleton et al., 2014; Gole and Wiesmuller, 2015). All the above disease characteristics, MLL-r, short latency and poor prognosis, strongly suggest that infant leukaemia and treatment-related leukaemia are sufficiently similar to allow for inferences to be made regarding tentative aetiological factors, molecular events and disease progression and manifestation.
A number of MLL-fusion products, such as MLL-AF9 and MLL-ENL, have shown leukemogenic potential in cord-blood stem cells. Although the MLL rearrangement is essential to develop leukaemia, it alone may not be sufficient and activation of cellular proliferation might be necessary for overt leukaemia (Nanya et al. 2015).
There are several animal models, in which MLL-AF4 fusion gene has been expressed (Chen et al 2006; Metzler et al 006; Krivtsov et al 2008; Bursen et al 2008; Tamai et al 2011). In all these models leukaemia is ultimately developed, but latency has been very protracted. In any case, one could conclude that the expression of the MLL-AF4 fusion gene is capable of developing leukaemia, but it is unknown whether facilitating or necessary changes are required during the long latency in mouse.
Gene engineered human HSPCs carrying MLL rearrangements showed that a subset of cells persisted over time and demonstrated a higher clonogenic potential in colony forming assay (Breese et al. 2015).
Transcription activator-like effector nuclease (TALEN)-mediated genome editing generated endogenous MLL-AF9 and MLL-ENL oncogenes in primary human HSPCs derived from human umbilical cord plasma (Buechele et al 2015). Engineered HSPCs displayed altered in vitro growth potential and induced acute leukaemias following transplantation in immunocompromised mice at a mean latency of 16 weeks. The leukemias displayed phenotypic and morphologic similarities with patient leukemia blasts, expressed elevated levels of crucial MLL-fusion partner target genes, displayed heightened sensitivity to DOT1L inhibition, and demonstrated increased oncogenic potential ex vivo and in secondary transplant assays.
Uncertainties and Inconsistencies
The MLL-AF4 knock-in mice develop leukaemia only after a prolonged latency (Chen et al 2006), thus not recapitulating the ‘pathognomonic’ feature of infant leukaemia. Also other animal models have been developed with similar results. Thus, an adequate experimental model for infant leukaemia is still in need.
The role of a reciprocal fusion gene AF4-MLL in leukemias is controversial: it has a transformation potential in animal model (Bursen et al 2010), but it is not expressed in all MLL-AF4 patients (Andersson et al 2015). The potential role of other reciprocal fusion genes has not been studied.
Beyond MLL rearrangements, activation of cellular proliferation by mutation or other (epi)genetic insults might be necessary for overt leukaemia. Further studies are necessary to fully understand which factors would contribute to convey a proliferative advantage, as observed in cells with MLL translocation, to leukaemia.
The product of MLL and MLL-r fusion genes are histone methyltransferases (HMT), which are the best known epigenetic mechanisms involved in MLL-r infant ALL. The main epigenetic mechanism is that MLL is a HMT with a H3K4me3 genome-wide profile. When MLL breaks and fuses to a partner it recruits DOT1L, the sole HMT H3K79me3 that thus regulates gene expression of the main MLL targets, namely HOX genes, MEIS, etc. Further epigenetic mechanisms recently proposed involved BCL2 activation through H3K70 methylation and H3K27 acetylation. Overall, the gene fusion products disrupt epigenetic pathways. The MLL-AF4 fusion protein binds to gene targets and is proposed to cause innapropiate gene activation through multiple trancription elongation and epigenetic mechanisms but further investigation is necessary to understand the exact connections between these factors and the enhancer activity.
Quantitative Understanding of the Linkage
Relationships between different fusion genes and subsequent leukemia types are incompletely understood. Although roughly 70-80 % of infant B-ALL leukemias carry MLL rearrangements, in 20-30 % of the cases there are no MLL rearrangements. In AML and T-ALL leukemia cases MLL rearrangements are even rarer.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
DNA topoisomerases are ubiquitous enzymes, which control the integrity of double-stranded DNA. They are thus key enzymes at all levels of living organisms. The available evidence suggest that important differences in sensitivity to topoisomerase inhibition might exist among different cell types, depending on the amount of proliferative burden, of the TopoII enzymes and on physiological repair processes. Mesodermal precursor or hematopoietic stem and progenitor cells (HSPCs) are rapidly dividing cells with a high content of TopoII and for these reasons they can be a sensitive target during a critical developmental window (Hernandez and Menendez 2016). In addition, evidence from micronuclei assay studies conducted in untreated and chemical-treated foetuses and newborns show that both the baseline and chemically induced micronuclei frequencies are higher in the foetuses and infants than in adults (Udroiu et al 2016). This is possibly indicating a greater sensitivity to genotoxic insult during development which can be due to the higher proliferation rate and lower ability of DNA repair of the hematopoietic stem cells. However, the role that the different microenvironments (foetal liver, infant bone marrow and adult bone marrow) during ontogenesis can exert on cell sensitivity cannot be ruled out (Udroiu et al. 2016). The existence of relevant interspecies differences is unknown, but it cannot be ruled out presently.
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