Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells

Nanya, Mai; Satō, Masaki; Tanimoto, Kousuke; Tozuka, Minoru; Mizutani, Shuki; Takagi, Motoki

doi:10.1371/journal.pone.0144540

Cited by 13 publications

(25 citation statements)

References 32 publications

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“…Epidemiological and genetic studies support the contention that the in utero origin of MA4 in infant B-ALL may be the result of transplacental exposures during pregnancy to quinone-based chemicals or dietary flavonoids [ 3 – 5 ]. This parallels the origin of therapy-related “secondary” leukemias harboring MLL - rearrangements [ 4 , 6 , 7 ] and is supported by the finding that MLL gene rearrangements can be induced in vitro and in vivo in hematopoietic stem/progenitor cells (HSPCs) at different ontogeny stages by etoposide, a topoisomerase-II inhibitor commonly used in chemotherapy regimens [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 81%

“…A recent in vivo study has reported that rearrangements of the MLL gene can only occur when cooperating defects in the DDR are in place. For instance, defective ATM, CHK2 and p53 signaling bypasses arrest of cells in G2/M phase, thus limiting the time for the cells to repair the damage before continuing to divide [ 11 , 32 ]. Because syngeneic cell lines were used it cannot be rule out that parallel or downstream insults cooperating with MLL fusions are also required to render further DNA damage vulnerability.…”

Section: Discussionmentioning

confidence: 99%

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Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair

et al. 2016

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The most frequent rearrangement of the human MLL gene fuses MLL to AF4 resulting in high-risk infant B-cell acute lymphoblastic leukemia (B-ALL). MLL fusions are also hallmark oncogenic events in secondary acute myeloid leukemia. They are a direct consequence of mis-repaired DNA double strand breaks (DNA-DSBs) due to defects in the DNA damage response associated with exposure to topoisomerase-II poisons such as etoposide. It has been suggested that MLL fusions render cells susceptible to additional chromosomal damage upon exposure to etoposide. Conversely, the genome-wide mutational landscape in MLL-rearranged infant B-ALL has been reported silent. Thus, whether MLL fusions compromise the recognition and/or repair of DNA damage remains unanswered. Here, the fusion proteins MLL-AF4 (MA4) and AF4-MLL (A4M) were CRISPR/Cas9-genome edited in the AAVS1 locus of HEK293 cells as a model to study MLL fusion-mediated DNA-DSB formation/repair. Repair kinetics of etoposide- and ionizing radiation-induced DSBs was identical in WT, MA4- and A4M-expressing cells, as revealed by flow cytometry, by immunoblot for γH2AX and by comet assay. Accordingly, no differences were observed between WT, MA4- and A4M-expressing cells in the presence of master proteins involved in non-homologous end-joining (NHEJ; i.e.KU86, KU70), alternative-NHEJ (Alt-NHEJ; i.e.LigIIIa, WRN and PARP1), and homologous recombination (HR, i.e.RAD51). Moreover, functional assays revealed identical NHEJ and HR efficiency irrespective of the genotype. Treatment with etoposide consistently induced cell cycle arrest in S/G2/M independent of MA4/A4M expression, revealing a proper activation of the DNA damage checkpoints. Collectively, expression of MA4 or A4M does neither influence DNA signaling nor DNA-DSB repair.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair

et al. 2016

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“…Also, murine studies point to the life stage-related susceptibility with regard to topo II poisoning. Nanya et al (2015) demonstrated that mouse foetal liver HSPCs were more susceptible to etoposide than maternal bone marrow mononuclear cells.…”

Section: Modifying Conditions During the Embryo-foetal Periodmentioning

confidence: 99%

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

et al. 2017

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Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.

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“…The MLL gene encodes a methyltransferase with activity for lysine 4 of histone H3 (H3K4), which mediates changes in chromatin associated with epigenetic transcriptional activation that plays an essential role in regulating gene expression during early development and hematopoiesis [ 66 ]. Rearrangements involving the MLL gene have been reported to occur only in mice with defects in DNA damage response and not in wild-type animals [ 67 ]. MLL -r functions as the initiating, and perhaps the sole driving, oncogenic event by dysregulating epigenetic and/or transcriptional programs [ 33 ] ( Figure 1 ).…”

Section: Pathobiology Of Pediatric Leukemiasmentioning

confidence: 99%

“…, benzoquinone), quinolone antibiotics, bioflavonoids present in some fruits and vegetables and some pesticides [ 7 , 33 , 68 ]. However, exposure to topoisomerase-II inhibitors is not sufficient per se for rearrangement of MLL , and the genetic background, such as mutations in the DNA damage response pathway, may influence the likelihood of MLL -r [ 67 ].…”

Section: Pathobiology Of Pediatric Leukemiasmentioning

confidence: 99%

Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms

Hernández

Menéndez

2016

IJMS

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Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events.

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Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells

Cited by 13 publications

References 32 publications

Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair

Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms

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