Laboratory characterization of the pediatric B/T subtype of mixed-phenotype acute leukemia: Report of a case series.

Objectives: Mixed-phenotype acute leukemia (MPAL) is a rare disease associated with difficulties in the correct lineage assignment of leukemic cells. One of the least common subtypes within this category is characterized by the simultaneous presence of B- and T-lineage-defining antigens. Each case of suspected B/T MPAL should be considered in light of all available laboratory and clinical data to avoid misdiagnosis.

Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation.

The first activation of gene expression during development (zygotic genome activation, ZGA) is accompanied by massive changes in chromosome organization. The connection between these two processes remains unknown. Using Hi-C for zebrafish embryos, we found that chromosome folding starts by establishing "fountains", novel elements of chromosome organization, emerging selectively at enhancers upon ZGA.

Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children-A Single Center Experience.

Acute promyelocytic leukemia (APL) pathogenesis is based on gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other family members or completely different genes.

APOBEC mutagenesis is low in most types of non-B DNA structures.

While somatic mutations are known to be enriched in genome regions with non-canonical DNA secondary structure, the impact of particular mutagens still needs to be elucidated. Here, we demonstrate that in human cancers, the APOBEC mutagenesis is not enriched in direct repeats, mirror repeats, short tandem repeats, and G-quadruplexes, and even decreased below its level in B-DNA for cancer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activity in inverted repeats (cruciform structures), where the impact of cytosine at the 3'-end of the hairpin loop is substantial.

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy.

We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.

Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes.

Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored.

High Rates of Genome Rearrangements and Pathogenicity of spp.

are pathogens originating within the lineage but frequently classified as a separate genus. genomes contain numerous insertion sequences (ISs) that lead to pseudogenisation of affected genes and an increase of non-homologous recombination. Here, we study 414 genomes of and strains to assess the contribution of genomic rearrangements to evolution.

Reprograming of sRNA target specificity by the leader peptide peTrpL in response to antibiotic exposure.

Trans-acting regulatory RNAs have the capacity to base pair with more mRNAs than generally detected under defined conditions, raising the possibility that sRNA target specificities vary depending on the specific metabolic or environmental conditions. In Sinorhizobium meliloti, the sRNA rnTrpL is derived from a tryptophan (Trp) transcription attenuator located upstream of the Trp biosynthesis gene trpE(G). The sRNA rnTrpL contains a small ORF, trpL, encoding the 14-aa leader peptide peTrpL.

Order and stochasticity in the folding of individual Drosophila genomes.

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes.

Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila.

How the nuclear lamina (NL) impacts on global chromatin architecture is poorly understood. Here, we show that NL disruption in Drosophila S2 cells leads to chromatin compaction and repositioning from the nuclear envelope. This increases the chromatin density in a fraction of topologically-associating domains (TADs) enriched in active chromatin and enhances interactions between active and inactive chromatin.

Activation of the alpha-globin gene expression correlates with dramatic upregulation of nearby non-globin genes and changes in local and large-scale chromatin spatial structure.

Background: In homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. Terminal erythroid differentiation results in dramatic upregulation of alpha-globin genes making their expression comparable to the rRNA transcriptional output. Little is known about the influence of the erythroid-specific alpha-globin gene transcription outburst on adjacent, widely expressed genes and large-scale chromatin organization.

Evolution of the Genome 3D Organization: Comparison of Fused and Segregated Globin Gene Clusters.

The genomes are folded in a complex three-dimensional (3D) structure. Some features of this organization are common for all eukaryotes, but little is known about its evolution. Here, we have studied the 3D organization and regulation of zebrafish globin gene domain and compared its organization and regulation with those of other vertebrate species.

Evolution of Brain Active Gene Promoters in Human Lineage Towards the Increased Plasticity of Gene Regulation.

Adaptability to a variety of environmental conditions is a prominent feature of Homo sapiens. We hypothesize that this feature can be explained by evolutionary changes in gene promoters active in the brain prefrontal cortex leading to a more flexible gene regulation network. The genotype-dependent range of gene expression can be broader in humans than in other higher primates.

Unraveling the mechanisms of chromatin fibril packaging.

Recent data indicate that eukaryotic chromosomes are organized into Topologically Associating Domains (TADs); however, the mechanisms underlying TAD formation remain obscure. Based on the results of Hi-C analysis performed on 4 Drosophila melanogaster cell lines, we have proposed that specific properties of nucleosomes in active and repressed chromatin play a key role in the formation of TADs. Our computer simulations showed that the ability of "inactive" nucleosomes to stick to each other and the lack of such ability in "active" nucleosomes is sufficient for spatial segregation of these types of chromatin, which is revealed in the Hi-C analysis as TAD/inter-TAD partitioning.

RNASurface: fast and accurate detection of locally optimal potentially structured RNA segments.

Motivation: During the past decade, new classes of non-coding RNAs (ncRNAs) and their unexpected functions were discovered. Stable secondary structure is the key feature of many non-coding RNAs. Taking into account huge amounts of genomic data, development of computational methods to survey genomes for structured RNAs remains an actual problem, especially when homologous sequences are not available for comparative analysis.

Comparative genomic analysis of T-box regulatory systems in bacteria.

T-box antitermination is one of the main mechanisms of regulation of genes involved in amino acid metabolism in Gram-positive bacteria. T-box regulatory sites consist of conserved sequence and RNA secondary structure elements. Using a set of known T-box sites, we constructed the common pattern and used it to scan available bacterial genomes.

Computational analysis of splicing errors and mutations in human transcripts.

Background: Most retained introns found in human cDNAs generated by high-throughput sequencing projects seem to result from underspliced transcripts, and thus they capture intermediate steps of pre-mRNA splicing. On the other hand, mutations in splice sites cause exon skipping of the respective exon or activation of pre-existing cryptic sites. Both types of events reflect properties of the splicing mechanism.

Abundance and functional diversity of riboswitches in microbial communities.

Background: Several recently completed large-scale enviromental sequencing projects produced a large amount of genetic information about microbial communities ('metagenomes') which is not biased towards cultured organisms. It is a good source for estimation of the abundance of genes and regulatory structures in both known and unknown members of microbial communities. In this study we consider the distribution of RNA regulatory structures, riboswitches, in the Sargasso Sea, Minnesota Soil and Whale Falls metagenomes.

A model of evolution with constant selective pressure for regulatory DNA sites.

Background: Molecular evolution is usually described assuming a neutral or weakly non-neutral substitution model. Recently, new data have become available on evolution of sequence regions under a selective pressure, e.g.