The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non- Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(- 4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.

There are 4 registries of hematopoietic cell transplantation in Japan; the Japan Society for Hematopoietic Cell Transplantation (JSHCT), Japanese Society of Pediatric Hematology, Japan Marrow Donor Program, and Japan Cord Blood Bank Network; each play an important role in society by reporting the number and outcomes of transplantations and contributing new findings obtained from studies on individual topics. However, there have been a number of issues with the difficulty of analyzing data in overlapping registries and multiple databases at centers affiliated with each of the 4 registry organizations. JSHCT was pivotal in orchestrating the computerization and unification of hematopoietic stem cell transplantation registries for the purpose of resolving these issues and providing a more accurate awareness of hematopoietic stem cell transplantations being performed in Japan. JSHCT played a central role in developing the "Transplant Registry Unified Management Program (TRUMP)" to enable transplantation institutes to manage patient information with emphases on convenience to institutes, safety of patient information, and quality of data management. While enhancing domestic registries, the program seeks to coordinate with other hematopoietic cell transplantation registries around the world to contribute to the development of registries throughout Asia.

Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

Summary:We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days posttransplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P Ͻ 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P = 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLAmatched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors. Bone Marrow Transplantation (2001) 28, 181-185.

IntroductionWilms tumor gene, WT1, is responsible for the tumorigenesis of a childhood renal neoplasm, Wilms tumor, which is thought to arise as a result of the inactivation of both alleles of the WT1 gene. 1,2 The WT1 gene has been considered a tumor-suppressor gene on the basis of findings such as intragenic deletions or mutations in Wilms tumor, germline mutations in patients with leukemia predisposition syndromes, and WT1-mediated growth suppression of Wilms tumor cells. [3][4][5][6][7] This gene encodes a zinc finger transcription factor involved in tissue development, in cell proliferation and differentiation, and in apoptosis. 8 The WT1 gene product represses the transcription of growth factor (platelet-derived growth factor ␣ chain, 9 colony-stimulating factor-1, 10 and insulinlike growth factor-II [IGF-II] 11 ) and growth factor receptor genes (IGF-IR 12 and EGFR 13 ), and the other genes (RAR-␣, 14 c-myb, 15 c-myc, 16 bcl-2, 16 ornithine decarboxylase, 17 and N-myc 18 ), whereas it activates the transcription of some genes (retinoblastoma suppressor-associated protein 46,20 and bcl-2 21 ). Unlike tumor-suppressor genes such as Rb and p53 that are ubiquitously expressed, WT1 gene expression is restricted to a limited set of tissues, including gonads, uterus, kidney, mesothelium, and hematopoietic progenitors. [22][23][24] WT1 knock-out mice have been shown to have defects in the urogenital system and to die at embryonic day 13.5, probably because of heart failure. 25 The WT1 gene was originally defined as a tumor-suppressor gene, as mentioned earlier. However, we recently proposed that the wild-type WT1 gene performs an oncogenic rather than a tumorsuppressor function in leukemogenesis and tumorigenesis in various types of solid tumors on the basis of the following findings: (1) high expression of the wild-type WT1 gene in leukemias [26][27][28][29][30][31] and various types of solid tumors, including ovarian tumors, Leydig cell tumors, mesothelioma, gastric cancer, colon cancer, lung cancer, and breast cancer 23,[32][33][34][35][36][37][38][39][40][41][42][43] ; (2) growth inhibition of leukemic 44,45 and solid tumor cells 41 by treatment with WT1 antisense oligomers; (3) promotion of cell growth, but blocking of cell differentiation, in the myeloid progenitor cell line 32D 46 and in normal bone marrow myeloid cells 47 as a result of constitutive WT1 gene expression caused by transfection with the wild-type WT1 gene; and (4) WT1 expression detected in most 7,12-dimethylbenzanthracene-induced erythroblastic leukemias and a tendency for cells with high levels of WT1 expression to develop into leukemias. 48 Stimulation in vitro of HLA-A2.1-positive or -A24.2-positive peripheral blood mononuclear cells with 9-mer WT1 peptides containing major histocompatibility complex (MHC) class 1 binding anchor motifs elicited WT1-specific cytotoxic T lymphocytes (CTLs). [49][50][51] These CTLs specifically killed WT1-expressing tumor cells in an HLA class 1-restricted manner and inhibited colony (1) cancer-testis ant...