Haematologica最新文献

The clinical and genetic features of type 2 von Willebrand disease (VWD) have been described, but genotype-phenotype correlations in large cohorts remain incompletely understood. We investigated the relationship between von Willebrand factor gene (VWF) variants and bleeding severity in a large, well-characterized cohort of type 2 VWD patients, aiming to identify genetic determinants underlying clinical variability. Comprehensive laboratory evaluation, VWF molecular testing, in silico analyses, and bleeding assessment using the ISTH bleeding assessment tool (ISTH-BAT) were performed. Among 371 genetically confirmed cases, ISTH-BAT scores were available for 274 individuals: 83 with type 2A, 69 with 2B, 106 with 2M, and 16 with 2N. The highest bleeding scores were observed in type 2A (median 7), followed by 2B (5), 2M (4), and 2N (4). A total of 67 distinct VWF variants were identified. Notably, we observed substantial variability in bleeding severity both across different variants causing the same VWD phenotypes and among individuals carrying the same VWF variant. ISTH-BAT scores were significantly higher in females than in males, and in adults compared to children. Among adults, but not children, bleeding scores differed significantly between some subtypes. No significant differences were observed between patients with blood group O and non-O. While certain mucocutaneous bleeding symptoms such as menorrhagia, cutaneous, and epistaxis were commonly observed across all type 2 subtypes, our data highlight important subtype-specific differences in bleeding phenotype profiles. This study provides one of the largest genotype-phenotype datasets in type 2 VWD, revealing marked variability in bleeding severity both across type 2 VWD subtypes and among patients with the same genetic variants.

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia cells and leukemic stem cells. STAT3 has also been shown to translocate to the mitochondria in acute myeloid leukemia cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for the mitochondrial functions of STAT3. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also results in significantly reduced engraftment potential of leukemia stem cells, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in acute myeloid leukemia.

The commitment of hematopoietic stem cells (HSC) to myeloid, erythroid, and lymphoid lineages is influenced by microenvironmental cues, and governed by cell-intrinsic and epigenetic characteristics that are unique to the HSC population. To investigate the nature of lineage commitment bias in human HSC, mitochondrial single-cell assay for transposase-accessible chromatin (ATAC)-sequencing was used to identify somatic mutations in mitochondrial DNA to act as natural genetic barcodes for tracking the ex vivo differentiation potential of HSC to mature cells. Clonal lineages of human CD34+ cells and their mature progeny were normally distributed across the hematopoietic lineage tree without evidence of significant skewing. To investigate commitment bias in vivo, mice were transplanted with limited numbers of long-term HSC (LT-HSC). Variation in the ratio of myeloid and lymphoid cells between donors was suggestive of a skewed output but was not altered by increasing numbers of LT-HSC. These data suggest that the variation in myeloid and lymphoid engraftment is a stochastic process dominated by the irradiated recipient niche with minor contributions from cell-intrinsic lineage biases of LT-HSC.