ALBERT

Description: Typical acute promyelocytic leukemia (APL) is associated with expression of the PML/RARα fusion protein resulting from chromosomal translocation t(15;17) and responsiveness to treatment with all-trans retinoic acid (ATRA). A few population of APL is associated with variant chromosomal translocations, t(11;17), t(5;17) and t(17;17). PLZF/RARα is the chimeric fusion protein resulting from the chromosomal translocation, t(11;17)(q23;q21). APL cells with PLZF/RARα have been reported to be unresponsive to ATRA-induced terminal differentiation clinically and experimentally. The molecular basis of unresponsiveness in PLZF/RARα-derived APL cells against ATRA explained by a rigid interaction between BTB/POZ domain of PLZF and a transcriptional co-repressor, N-CoR. PLZF/RARα contains BTB/POZ domain in its N-terminus. BTB/POZ domain is developmentally conserved among various species, and recently several BTB/POZ-containing molecules have been reported to function as substrate-specific adaptors for Cul3-based E3 ubiquitin ligase. Here we examined the possibility that PLZF/RARα functions as an E3 ligase. We performed the series of transient transfection analysis. By immunoprecipitation assay, PLZF/RARα associated with Cul3, and PLZF/RARα also associated with RXRα. PLZF/RARα accelerated an ubiquitin-dependent degradation of RXRα, and resulted in the decreased expression of RXRα. This degradation of RXRα was dependent on the expression level of PLZF/RARα. On the contrary, co-expression of dominant negative form of Cul3 with PLZF/RARα resulted in the restored expression of RXRα. When we expressed PML/RARα, PLZF or PLZF/RARαΔBTB, the accelerated degradation of RXRα was not observed. In RARα-responsive luciferase assay, PLZF/RARα repressed ATRA response. Consistent with the result that PLZF/RARαΔBTB did not down-regulate the expression of RXRα, PLZF/RARαΔBTB did not repress ATRA response. In addition, the transduction of recombinant RXRα molecule into PLZF/RARα expressing cells partially restored ATRA-responsiveness. Collectively, we suggest that ATRA resistance in PLZF/RARα-positive cells is explained by the novel function of PLZF/RARα molecule.

Description: Appearance of anti-hepatitis B surface antigen antibody (anti-HBs) and clearance of hepatitis B virus (HBV) from serum usually indicates resolution of hepatitis in patients infected with HBV. However, in most patients in whom HBV has been eliminated from serum, HBV DNA is still detectable in the liver using polymerase chain reaction. Reactivation of this dormant HBV in the liver is known as reverse seroconversion (RS). Previously, we reported that HBV-RS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was a frequent late-onset complication that can be predicted by careful monitoring of progressive disappearance of anti-HBs. RS hepatitis after allo-HSCT is thought to be a phenomenon caused by naive donor immunity after loss of recipient-oriented immunity against HBV. We speculated that vaccination could prevent reactivation of HBV in allo-HSCT recipients. Safety and efficacy of recombinant HBV vaccine in allo-HSCT recipients have already been confirmed. We studied HBV serological markers in 23 patients with anti-HBs and/or anti-HBc before allo-HSCT who were followed for more than 1 year. Patients’ characters are following; Age at HSCT 22 to 65 (median, 38) years; M:F ratio 14:9; Hematological disorders CML 6, AML 1, ALL 4, MDS 4, SAA 2, NHL 4, MM 1 and CAEBV 1; Serological markers anti-HBc(+) and anti-HBs(+) 17, anti-HBc(+) and anti-HBs(−) 3, anti-HBc(−) and anti-HBs(+) 3. No patients had a prior history of vaccination or HBV-specific immunoglobulin usage. All patients were negative for hepatitis B surface antigen (HBsAg) and were considered to have previous HBV infection. The follow-up period varied from 12 to 116 (median, 36) months. Eighteen patients were followed without intervention. Five patients were vaccinated with recombinant HBV vaccine by the standard three-dose protocol after cessation of immunosuppressant administration. RS was defined as disappearance of anti-HBs and appearance of HBsAg and HBV-DNA with or without clinical hepatitis. Progressive decreases in anti-HBs titer were observed in all pre-HSCT anti-HBs-positive recipients. In 18 of the 20 patients with pre-HSCT anti-HBs, anti-HBs titer decreased to less than the protective value (

Description: Thalidomide (Thal) alone or in combination with steroids achieves responses even in the setting of refractory multiple myeloma (MM), however, responses are still limited. The precise mechanism of Thal action is unknown, further, no distinct marker, which could prognosticate the efficacy of Thal, is known. Therefore, we evaluated the correlation between the efficacy of Thal and the potent prognostic factors in patients with refractory MM. Ten patients with refractory MM received Thal at doses of 50 or 100 mg per day and steroids, either dexamethasone (Dex) or prednisolone (PSL). Dex was administrated 20 mg per day, 4 days every 28 days, and PSL was administrated 10 mg per day. The median age was 71.5 years (range, 62–79 years) and 20 % were man, and all patients were diagnosed as clinical stage IIIA based on the Durie and Salmon classification. The therapeutic response was assessed according to the modified criteria of Southwest Oncology Group (SWOG). Among 10 patients, 7 patients were the responders; 2 had complete remission, 3 had partial remission, and 2 had minimal remission. There were no differences in the pretreatment characteristics of responders and nonresponders (age, sex, type and concentration of serum and/or urine monoclonal component, international prognostic index, presence of bone lesion, and chromosomal abnormalities). However, flow cytometric evaluation of the myeloma cells revealed that CD56, which is one of the adhesion molecules N-CAM, expressed more than 45 % in all responders, while those expressed less than 5 % in all nonresponders (84 ± 19 (±SD) % v/s 4 ± 2 %, P=0.017). Furthermore, CD56 expression of the myeloma cells was reduced from 84% to 70 ± 32 % after Thal therapy in all evaluated responders (P =0.048). These results suggest that CD56 expression of the myeloma cells could be the potent prognostic marker of the Thal efficacy. Moreover, it was reported that Thal reduced the expression of cell adhesion molecules, such as LFA-1 and ICAM-1, and abrogated the binding of MM cells to bone marrow stromal cells, that triggered the secretion of interleukin-6 and vascular endothelial growth factor. Taken together, it was suggested that Thal reduced the expression of CD56 and altered the MM cell adhesion to bone marrow stromal cells, and that could be one of the pathogenesis of anti-MM activity of Thal.