Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.

The splicing factor SF3B1 is the most frequently mutated gene in myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberrant splicing events in many downstream target genes were identified and cryptic 3' splice site usage was a frequent event in SF3B1-mutant MDS. The iron transporter ABCB7 is a well-recognized candidate gene showing marked downregulation in MDS with RS. Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3' splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA. Treatment of cultured SF3B1-mutant MDS erythroblasts and a CRISPR/Cas9-generated SF3B1-mutant cell line with the nonsense-mediated decay (NMD) inhibitor cycloheximide showed that the aberrantly spliced ABCB7 transcript is targeted by NMD. We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS

Alumina scale formation on a powder metallurgical FeCrAl alloy (Kanthal APMT) at 900-1100\ub0C in dry O2 and in O2 + H2O

A Rapidly Solidified Powder (RSP) metallurgical FeCrAl alloy, Kanthal APMT, was exposed in dry and humid O-2 for 72 h at 900-1,100 A degrees C. The formed oxide scales were characterized using gravimetry in combination with advanced analysis techniques (SEM, EDX, TEM, XRD, AES and SIMS). The oxide scales were at all exposures composed of two-layered alpha-Al2O3 scales exhibiting a top layer of equiaxed grains and a bottom layer containing elongated grains. A Cr-rich zone, originating in the native oxide present before exposure, separated these two layers. The top alpha-Al2O3 layer is suggested to have formed by transformation of outwardly grown metastable alumina, while the inward-grown bottom alpha-Al2O3 layer had incorporated small Zr-, Hf- and Ti-rich oxide particles present in the alloy matrix. The scale also contained larger Y-rich oxide particles. Furthermore, in the temperature range studied, the presence of water vapour accelerated alloy oxidation somewhat and affected scale morphology