Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells

Bueno, Clara; Catalina, Purificación; Melén, Gustavo J.; Montes, Rosa; Sánchez, Laura; Ligero, Gertrudis; García‐Pérez, José L.; Menéndez, Pablo

doi:10.1093/carcin/bgp169

Cited by 67 publications

(93 citation statements)

References 35 publications

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“…Most of our understanding of transformation by MLL-AF4 has come from murine models [2][3][4]26,27 and human stem cell systems. 1,[28][29][30][31][32][33] These have provided important insights into the likely mode of action of MLL-AF4, but the in vivo leukemias produced in these studies do not recapitulate the actual human disease phenotype and latency, and therefore MLL-AF4 leukemogenesis remains particularly difficult to model. This suggests that in order to develop a bona fide MLL-AF4 model by which to further understand the disease pathogenesis and to screen novel small-molecule compounds, additional oncogenic events such as FLT3 constitutive activation 8 or the derivative AF4-MLL seem to be required to develop ALL.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n ¼ 49) or T-ALL (n ¼ 5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1 þ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4 þ B-ALL but also ETV6-RUNX1 þ , BCR-ABL þ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P ¼ 0.002) and disease-free survival (DFS; 0 vs 43%; P ¼ 0.03) in MLL-AF4 þ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age414 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4 þ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4 þ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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“…3) and can differ between cell lines (Supplementary Tables 22 and 23). Knowledge of CNVs can help researchers avoid unexpected genomic changes [35][36][37] when using nucleases in duplicated regions. CNVs can be clone-specific as gene copy numbers in a single cell line vary considerably during growth media adaptation or after several cell passages 29,38 .…”

Section: Genome Annotationmentioning

confidence: 99%

Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome

Lewis¹,

et al. 2013

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Chinese hamster ovary (CHO) cells, first isolated in 1957, are the preferred production host for many therapeutic proteins. Although genetic heterogeneity among CHO cell lines has been well documented, a systematic, nucleotide-resolution characterization of their genotypic differences has been stymied by the lack of a unifying genomic resource for CHO cells. Here we report a 2.4-Gb draft genome sequence of a female Chinese hamster, Cricetulus griseus, harboring 24,044 genes. We also resequenced and analyzed the genomes of six CHO cell lines from the CHO-K1, DG44 and CHO-S lineages. This analysis identified hamster genes missing in different CHO cell lines, and detected >3.7 million single-nucleotide polymorphisms (SNPs), 551,240 indels and 7,063 copy number variations. Many mutations are located in genes with functions relevant to bioprocessing, such as apoptosis. The details of this genetic diversity highlight the value of the hamster genome as the reference upon which CHO cells can be studied and engineered for protein production.

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“…12,13 The MLL rearrangements may in fact be the result of transplacental exposures to substances that alter the function of DNA topoisiomerase II, a DNA repairing enzyme highly expressed during embryonic development. [14][15][16][17][18][19][20] Among these genotoxic compounds, the etoposide (VP16) is the best studied. Etoposide is a topoisomerase II inhibitor commonly used in chemotherapy cocktails and is responsible for 5-15% of the therapy-related acute leukemias.…”

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confidence: 99%

“…Human ESCs (hESCs) hold the promise to become a powerful tool for drug screening and toxicity but also to determine the spatial-temporal onset of diseases that are known to arise in utero. 16,[27][28][29] Etoposide induces MLL rearragements in hESCs and CB-CD34 þ hematopoietic stem/progenitor cells…”

mentioning

confidence: 99%

“…16 We wanted to address whether (i) very low doses of etoposide promote MLL rearrangements in hESCs and hESC-derived hematopoietic cells; (ii) MLL rearrangements are sufficient to confer hESCs with a selective proliferation/survival advantage and; (iii) whether continuous exposure to very low doses of etoposide predisposes hESCs to acquire other chromosomal abnormalities. Interestingly, exposure to a single low dose of etoposide induced a pronounced cell death in undifferentiated hESCs but not in postnatal CD34 þ HSCs.…”

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confidence: 99%

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Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

et al. 2010

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Infant acute lymphoblastic leukemia (ALL) involving mixedlineage leukemia (MLL) fusions has attracted a huge interest in basic and clinical research because of its prenatal origin, mixed-lineage phenotype, dismal prognosis and extremely short latency. Over 90% of infant ALLs are pro-B ALL harboring the leukemic fusion MLL-AF4. Despite the fact that major achievements have provided a better understanding about the etiology of infant MLL-AF4 þ ALL over the last two decades, key questions remain unanswered. Epidemiological and genetic studies suggest that the in utero origin of MLL rearrangements in infant leukemia may be the result of prenatal exposure to genotoxic compounds. In fact, chronic exposure of human embryonic stem cells (hESCs) to etoposide induces MLL rearrangements and makes hESC more prone to acquire subsequent chromosomal abnormalities than postnatal CD34 þ cells, linking embryonic exposure to topoisomerase II inhibitors to genomic instability and MLL rearrangements. Unfortunately, very little is known about the nature of the target cell for transformation. Neuron-glial antigen 2 expression was initially claimed to be specifically associated with MLL rearrangements and was recently shown to be readily expressed in CD34 þ CD38 þ , but not CD34 þ CD38À cells suggesting that progenitors rather than stem cells may be the target cell for transformation. Importantly, the recent findings showing that MLL-AF4 rearrangement is present and expressed in mesenchymal stem cells from infant patients with MLLAF4 þ ALL challenged our current view of the etiology and cellular origin of this leukemia. It becomes therefore crucial to determine where the leukemia relapses come from and how the tumorstroma relationship is defined at the molecular level. Finally, MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far. It is likely that the current disease models are missing some essential ingredients of leukemogenesis in the human embryo/ fetus. We thus propose modeling MLL-AF4 þ infant pro-B ALL using prenatal hESCs.

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Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells

Cited by 67 publications

References 35 publications

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

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