CXCL8 secreted by immature granulocytes inhibits WT hematopoiesis in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate.

Extracting, filtering and simulating cellular barcodes using CellBarcode tools.

Identifying true DNA cellular barcodes among polymerase chain reaction and sequencing errors is challenging. Current tools are restricted in the diversity of barcode types supported or the analysis strategies implemented. As such, there is a need for more versatile and efficient tools for barcode extraction, as well as for tools to investigate which factors impact barcode detection and which filtering strategies to best apply.

ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination.

Background: Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma both portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD are unclear. The Abelson (ABL) tyrosine kinase family members, ABL1 and ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, and chemotherapy resistance, and are upstream mediators of the oncogene in fibroblasts and lung cancer cells.

Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma.

Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the molecular basis of EV release remains poorly understood.

TP53 mutation is enriched in colorectal cancer liver metastasis in the context of polyclonal seeding.

Cancer metastasis accounts for the majority of cancer motility burden. For colorectal cancer (CRC), the liver is the most common site of distant metastasis. It is still little known that cancer genomic mutations, which are a cell-intrinsic and heritable property, are enriched in CRC liver metastasis.

H3K27me3 conditions chemotolerance in triple-negative breast cancer.

The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood.

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells.

The cytokine erythropoietin (EPO) is a potent inducer of erythrocyte development and one of the most prescribed biopharmaceuticals. The action of EPO on erythroid progenitor cells is well established, but its direct action on hematopoietic stem and progenitor cells (HSPCs) is still debated. Here, using cellular barcoding, we traced the differentiation of hundreds of single murine HSPCs, after ex vivo EPO exposure and transplantation, in five different hematopoietic cell lineages, and observed the transient occurrence of high-output myeloid-erythroid-megakaryocyte-biased and myeloid-B-cell-dendritic cell-biased clones.

To portray clonal evolution in blood cancer, count your stem cells.

Clonal evolution, the process of expansion and diversification of mutated cells, plays an important role in cancer development, resistance, and relapse. Although clonal evolution is most often conceived of as driven by natural selection, recent studies uncovered that neutral evolution shapes clonal evolution in a significant proportion of solid cancers. In hematological malignancies, the interplay between neutral evolution and natural selection is also disputed.

Comparing Phylogenetic Approaches to Reconstructing Cell Lineage From Microsatellites With Missing Data.

Due to the imperfect fidelity of DNA replication, somatic cells acquire DNA mutations at each division which record their lineage history. Microsatellites, tandem repeats of DNA nucleotide motifs, mutate more frequently than other genomic regions and by observing microsatellite lengths in single cells and implementing suitable inference procedures, the cell lineage tree of an organism can be reconstructed. Due to recent advances in single cell Next Generation Sequencing (NGS) and the phylogenetic methods used to infer lineage trees, this work investigates which computational approaches best exploit the lineage information found in single cell NGS data.

A track of the clones: new developments in cellular barcoding.

International experts from multiple disciplines gathered at Homerton College in Cambridge, UK from September 12-14, 2018 to consider recent advances and emerging opportunities in the clonal tracking of hematopoiesis in one of a series of StemCellMathLab workshops. The group included 35 participants with experience in the fields of theoretical and experimental aspects of clonal tracking, and ranged from doctoral students to senior professors. Data from a variety of model systems and from clinical gene therapy trials were discussed, along with strategies for data analysis and sharing and challenges arising due to underlying assumptions in data interpretation and communication.

Mouse decellularised liver scaffold improves human embryonic and induced pluripotent stem cells differentiation into hepatocyte-like cells.

Liver transplantation is the definitive treatment of liver failure but donor organ shortage limits its availability. Stem cells are highly expandable and have the potential to differentiate into any specialist cell. Use of patient-derived induced Pluripotent Stem Cells (hiPSCs) has the additional advantage for organ regeneration therapies by removing the need for immunosuppression.

Vps33b is crucial for structural and functional hepatocyte polarity.

Background & Aims: In the normal liver, hepatocytes form a uniquely polarised cell layer that enables movement of solutes from sinusoidal blood to canalicular bile. Whilst several cholestatic liver diseases with defects of hepatocyte polarity have been identified, the molecular mechanisms of pathogenesis are not well defined. One example is arthrogryposis, renal dysfunction and cholestasis syndrome, which in most patients is caused by VPS33B mutations.

Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.

Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. However, the mechanism and contribution of collagen modifications that occur outside the endoplasmic reticulum and Golgi are not understood. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types.