Changing insights in the diagnosis and classification of autosomal recessive and dominant von Willebrand diseases 1980-2015

The European Clinical Laboratory and Molecular(ECLM) criteria define 10 distinct Willebrand diseases(VWD) recessive type 3, severe 1, 2C and 2N; dominant VWD type 1 secretion/clearance defect, 2A, 2B, 2E, 2M and 2D; and mild type 1 VWD(usually carriers of recessive VWD). Recessive severe 1 and 2C VWD are characterized by secretion and multimerization defects caused by mutations in the D1-D2 domain. Recessive 2N VWD is a mild hemophilia due to D'-FVIII-von Willebrand factor(VWF) binding site mutations. Dominant 2E VWD caused by heterozygous missense mutations in the D3 domain is featured by a secretion-clearancemultimerization VWF defect. Dominant VWD type 2M due to loss of function mutations in the A1 domain is characterized by decreased ristocetin-induced platelet aggregation and VWF RCo, normal VWF multimers and VWF CB, a poor response of VWF RCo and good response of VWF CB to desmopressin(DDAVP). Dominant VWD type 2A induced by heterozygous mutations in the A2 domain results in hypersensitivity of VWF for proteolysis by ADAMTS13 into VWF degradationproducts, resulting in loss of large VWF multimers with triplet structure of each individual VWF band. Dominant VWD type 2B due to a gain of function mutation in the A1 domain is featured by spontaneous interaction between platelet glycoprotein Ib(GPIb) and mutated VWF A1 followed by increased proteolysis with loss of large VWF multimers and presence of each VWF band. A new category of dominant VWD type 1 secretion or clearance defect due to mutations in the D3 domain or D4-C1-C5 domains consists of two groups Those with normal or smeary pattern of VWF multimers.

ETV2 mediates endothelial transdifferentiation of glioblastoma

Glioblastoma multiforme(GBM)is characterized by extensive endothelial hyperplasia.Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells(endotransdifferentiation).The molecular mechanism underlying this process remains poorly defined.Here,we show that the expression of ETS variant 2(ETV2),a master regulator of endothelial cell development,is highly correlated with malignancy.Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+GBM/neural stem cells to an endothelial lineage.Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2,in addition to activating vascular genes,represses proneural genes to direct endo-transdifferentiation.Since endotransdifferentiation by ETV2 is VEGF-A independent,it likely accounts for the observed resistance of GBM tumor cells to antiangiogenesis therapy.Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM.