Objective-The transmembrane ligand ephrin-B2 and its receptor tyrosine kinase EphB4 are specifically expressed on arterial and venous endothelial cells, respectively, and bidirectional signals mediated by both proteins play an important role in vascular development. However, how such bidirectional signals are required for cell-cell adhesion or repulsion remains unclear. Methods and Results-Using a cell line and sorted primary endothelial cells, we show that ephrin-B2 forward signaling through the EphB4 receptor inhibits cell adhesion, whereas EphB4 reverse signaling by the transmembrane ephrin-B2 ligand does not. Cell migration is also inhibited on immobilized ephrin-B2-Fc but not on EphB4-Fc protein. Key Words: ephrin-B2 Ⅲ EphB4 Ⅲ cell adhesion Ⅲ spreading Ⅲ vascular development D uring vascularization and the maintenance of blood vessel integrity, cell adhesiveness and motility change at the endothelial cell level. Endothelial cells adhere to each other and to the extracellular matrix through interactions involving cell surface proteins. Changes in morphogenesis during vascularization can be considered a consequence of precise spatio-temporal expression of cell surface molecules controlling cell adhesion and motility. Several cell surface receptors that trigger intercellular signals regulating cell proliferation, differentiation, or migration in vascular development have been identified and characterized. 1-3 The Eph receptor tyrosine kinases and their ephrin ligands mediate numerous developmental processes in both invertebrates and vertebrates. 4 Multiple functions of Eph receptors throughout embryonic development are suggested by complex and highly dynamic expression patterns as well as by experimental evidence. 5 The ephrins, unlike ligands for other receptor tyrosine kinases, must be membrane-anchored to activate Eph receptors. 6 Based on how they are tethered to the membrane, ephrins are divided into 2 subclasses. The 5 members of the ephrin-A subclass (ephrin-A1 to -A5) are tethered via a glycosylphosphatidylinositol (GPI) anchor, whereas the 3 members of the ephrin-B subclass (ephrin-B1 to -B3) have a transmembrane domain and highly conserved cytoplasmic domains. Ephrin-B ligands interact primarily with the B subset of Eph receptors, which consist of at least 6 members. 6,7 A characteristic of ephrin/Eph signaling is the potential for bidirectional signaling, that is, classical forward signaling by the Eph receptor via its intrinsic tyrosine kinase activity and reverse signaling by the transmembrane ephrin-B ligand via its cytoplasmic domain. Conclusions-EphrinRecent work shows that ephrin-B2 ligand and its cognate EphB4 receptor are required for vascular development. Targeted disruption of the ephrin-B2 gene in mice leads to embryonic lethality at embryonal day (E) 10.5, attributable to a defect in both arterial and venous vessel remodeling. 8,9 This defect is accompanied by a failure of intercalation between arteries and veins. EphB4 homozygous mutants have a similar phenotype with ephrin-B2 homozygou...

We examined the incidence and prognostic effect of IDH1 and IDH2 mutations in 233 Japanese adults with acute myeloid leukemia (AML). IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%, 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were associated with normal karyotype AML, cytogenetic intermediate-risk group, and NPM1 mutations. Five-year overall survival (OS) rates were significantly lower (15.6%) in patients harboring the IDH mutations than in patients lacking the IDH mutation (32.0%) in the entire cohort of AML (P = 0.005). Among patients aged 59 yr or younger with IDH mutations, 5-yr OS in patients who underwent allogeneic stem cell transplantation (SCT) was significantly higher than that in those not receiving allogeneic SCT (50% vs. 10.6%, P = 0.020). Of 51 patients with NPM1 mutations, there was no significant difference in 5-yr OS rates between patients with and those without the IDH mutations. In contrast, among 175 patients lacking the NPM1 mutations, 5-yr OS rate in patients with IDH mutations was significantly lower than that in those without IDH mutations (0% vs. 34.7%, P = <0.001). These data suggest that IDH mutations have an unfavorable effect in AML, especially AML with the NPM1 wild type and younger AML patients with IDH mutations may benefit from allogeneic SCT.

Dendritic cells (DCs) are believed to be the most potent antigen-presenting cells and may be important in the induction of anti-leukemia specific T cell responses. In this preliminary clinical study, a patient with chronic phase chronic myelogenous leukemia (CML) was vaccinated with autologous leukemic DCs following autologous peripheral blood stem cell transplantation (PBSCT). In an in vitro study, leukemic DCs were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α α α α, and interleukin-4 from granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC fraction of this patient, and were found to be Ph1

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