A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data

E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family.

E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. This role for E2F4 is independent of the RB family. Furthermore, E2F4 functionally interacts with chromatin regulators associated with gene activation and we observed decreased histone acetylation at the promoters of cell cycle genes and E2F targets upon loss of E2F4 in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that provide insights into the biology of rapidly dividing cells

Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing

Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells

The Origin and Evolution of Mutations in Acute Myeloid Leukemia

SummaryMost mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse

Possible Uses of Camp in Interpretation of Czech Contemporary Cultural Background

Proposed dissertation is focusing on specific eccentric aesthetics based on hyperboles, ambivalent meanings and ironic attitude, which in Anglo-American background is so called camp derived from French. Camp origin can be found on the court of Louis XIV, where we can notice passionate tries to cultivate affected court-style culminating in baroque metaphor of the world as a theatre. Due to impact of modernity and postmodernity, scope of the camp extended to various cultural spheres and phenomenon began to corelate through its eccentricity with common marginality, respectively with something what is different from "normality" and "genuineness" also settled schemes of perception or ways of historical reflection. Goal of proposed dissertation is based on theoretical-historical interpretations to trace mentions of camp (mainly in literature) with focus on Czech background, where its rich interpretational potential can clarify most of social-cultural tendencies

Procitnutí jiné lásky. Rezonance tématu sexuální jinakosti v české divadelní tvorbě.

The present rigorous thesis focuses on the representations of sexuality and otherness in Czech culture, mainly on representations of ?queer love? in Czech theatre. Its aims are to analyse and to compare theatre plays which have been resonating in Czech and Czechoslovak social discourse since the end of 19th century. The research focuses on Czech original plays as well as foreign plays, which have been staged in Czech theatres. The analysis and the comparation also include play reviews and other texts and facts. For that purposes, it is relevant to apply theories of ?new historicism?, the performative concept of representation and the Czech and Czechoslovak everyday history. The results of the research describe transformation of sexuality and otherness and their Czech theatre representations in cultural and historical fields

The Representation of Men with Homosexual Orientation in Czech and Slovak Contemporary Drama

The present thesis focuses on the representations of gays in Czech and Slovak contemporary theater plays. Its aim is to analyze the queer and campy aspects of the representations of gays in the mainstream plays and uncover the principles of creation of the gay character in the structure of dramatic Arts. The results of analysis explain the integrative mode of representation of gays in Czech and Slovak contemporary plays

The Role of a Text in Dramatic Art.

The present BA thesis focuses on the role and the nature of a text in dramatic Arts and the relation of a dramatic text and a theater performance. Its aim is to demonstrate the place of dramatic text in the structure of dramatic Arts and important meaning of stage directions. The method of comparison is used in this BA thesis to introduce dramatic Arts in the context of czech aesthetics and semiotics of theater