Affixin interacts with α-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell–substrate interaction

The linking of integrin to cytoskeleton is a critical event for an effective cell migration. Previously, we have reported that a novel integrin-linked kinase (ILK)–binding protein, affixin, is closely involved in the linkage between integrin and cytoskeleton in combination with ILK. In the present work, we demonstrated that the second calponin homology domain of affixin directly interacts with α-actinin in an ILK kinase activity–dependent manner, suggesting that integrin–ILK signaling evoked by substrate adhesion induces affixin–α-actinin interaction. The overexpression of a peptide corresponding to the α-actinin–binding site of affixin as well as the knockdown of endogenous affixin by small interference RNA resulted in the blockade of cell spreading. Time-lapse observation revealed that in both experiments cells were round with small peripheral blebs and failed to develop lamellipodia, suggesting that the ILK–affixin complex serves as an integrin-anchoring site for α-actinin and thereby mediates integrin signaling to α-actinin, which has been shown to play a critical role in actin polymerization at focal adhesions

Central Nervous System Relapse of Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

AbstractLittle information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P = .029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P = .042), the history of CNS invasion before HSCT (RR = 5.62, 95% CI = 2.62-12.0, P = 9.2 × 10−6), and the prophylactic intrathecal chemotherapy after HSCT (RR = 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients

Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia.

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005