Increased MLL gene rearrangements in amniocytes from fetuses of mothers who smoke

Chica, Rosa Ana de la; Mediano, C.; Salido, Marta; Espinet, Blanca; Manresa, Josep María; Solé, Françesc

doi:10.1016/j.leukres.2011.04.010

Cited by 5 publications

(1 citation statement)

References 10 publications

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“…As MLL rearrangements in these patients can arise during in utero fetal hematopoiesis (Gale et al, 1997 ), prenatal exposure and consequently lifestyle of the mother are highly relevant for development of this type of leukemia. Increased MLL rearrangements were indeed observed in amniocytes from long-term smokers in a small prospective study (de la Chica et al, 2011 ), as well as a statistically significant association between intake of hormones during pregnancy and risk of in utero MLL rearrangements in a study enrolling several 100 children (Pombo-de-Oliveira et al, 2006 ). Estrogen, in particular, was demonstrated to induce MLL breakage and rearrangements in cultured lymphoblastoid cells (Schnyder et al, 2009 ).…”

Section: Incidence and Risk Of Mll Rearrangementsmentioning

confidence: 92%

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

Gole

Wiesmüller

2015

Front. Cell Dev. Biol.

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Despite manifold efforts to achieve reduced-intensity and -toxicity regimens, secondary leukemia has remained the most severe side effect of chemotherapeutic cancer treatment. Rearrangements involving a short telomeric <1 kb region of the mixed lineage leukemia (MLL) gene are the most frequently observed molecular changes in secondary as well as infant acute leukemia. Due to the mode-of-action of epipodophyllotoxins and anthracyclines, which have widely been used in cancer therapy, and support from in vitro experiments, cleavage of this MLL breakpoint cluster hotspot by poisoned topoisomerase II was proposed to trigger the molecular events leading to malignant transformation. Later on, clinical patient data and cell-based studies addressing a wider spectrum of stimuli identified cellular stress signaling pathways, which create secondary DNA structures, provide chromatin accessibility, and activate nucleases other than topoisomerase II at the MLL. The MLL destabilizing signaling pathways under discussion, namely early apoptotic DNA fragmentation, transcription stalling, and replication stalling, may all act in concert upon infection-, transplantation-, or therapy-induced cell cycle entry of hematopoietic stem and progenitor cells (HSPCs), to permit misguided cleavage and error-prone DNA repair in the cell-of-leukemia-origin.

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Section: Incidence and Risk Of Mll Rearrangementsmentioning

confidence: 92%

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

Gole

Wiesmüller

2015

Front. Cell Dev. Biol.

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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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Transplacental exposure to carcinogens and risks to children: evidence from biomarker studies and the utility of omic profiling

Botsivali

Kyrtopoulos

2019

Arch Toxicol

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Increased MLL gene rearrangements in amniocytes from fetuses of mothers who smoke

Cited by 5 publications

References 10 publications

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

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

Transplacental exposure to carcinogens and risks to children: evidence from biomarker studies and the utility of omic profiling

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