PIWIL4 Acts as a piRNA Binding, Epigenetically Active and Growth Regulatory Protein in Human Acute Myeloid Leukemia

Piwi proteins are critically important for maintaining the self-renewing stem cell population in lower organisms through epigenetic silencing of transposable elements via DNA methylation and H3K9me3 marks, in close interaction with a novel class of non-coding RNA called piwi interacting RNA (piRNA)

A Case of Monozygotic Twins: The Value of Discordant Monozygotic Twins in Goldenhar Syndrome—OMIM%164210

Goldenhar syndrome is a rare developmental disorder characterised by hemifacial microsomia, epibulbar tumours, ear malformation, and vertebral anomalies. As monozygotic (MZ) twins are believed to be genetically identical, discordance for disease phenotype between MZ twins varies with craniofacial anomalies, cardiac, vertebral, and central nervous system defects sporadically. We report a case of monozygotic female twins discordant for Goldenhar syndrome with hemifacial microsomia and the dysplasia of auricular pinna

Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors.

Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis since imbalanced production of ROS may lead to oxidative stress and cell death. The anti-oxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress-induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that it is essential for preventing RIP3 dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation. This results in necroptosis, which occurs independently of TNFα activation. While genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4 deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as so far unrecognized unconventional upstream signaling activators of RIP3-dependent necroptosis

Combined deficiency in glutathione peroxidase 4 and vitamin E causes multi-organ thrombus formation and early death in mice.

Rationale: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. Objective: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. Methods and Results: Endothelial-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. By stark contrast, aortic explants from endothelial-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Mice were therefore fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, about 80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane as well as endothelial cell death in multiple organs which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies including heart failure, renal and splenic micro-infarctions or paraplegia. Conclusions: Here we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability

The leukemogenicity of Hoxa9 depends on alternative splicing.

Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced AML after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms