Id1 immortalizes hematopoietic progenitors in vitro and promotes a myeloproliferative disease in vivo.

Id1 is frequently overexpressed in many cancer cells, but the functional significance of these findings is not known. To determine if Id1 could contribute to the development of hematopoietic malignancy, we reconstituted mice with hematopoietic cells overexpressing Id1. We showed for the first time that deregulated expression of Id1 leads to a myeloproliferative disease in mice, and immortalizes myeloid progenitors in vitro. In human cells, we demonstrate that Id genes are expressed in human acute myelogenous leukemia cells, and that knock down of Id1 expression inhibits leukemic cell line growth, suggesting that Id1 is required for leukemic cell proliferation. These findings established a causal relationship between Id1 overexpression and hematologic malignancy. Thus, deregulated expression of Id1 may contribute to the initiation of myeloid malignancy, and Id1 may represent a potential therapeutic target for early stage intervention in the treatment of hematopoietic malignancy.

Transplantation of peripheral blood stem cells mobilized by intensified consolidation and granulocyte colony-stimulating factor in acute leukemia.

The purpose of this study was to evaluate the feasibility and efficacy of autologous transplantation of peripheral blood stem cells (PBSC) mobilized with high-dose consolidation chemotherapy and granulocyte colony-stimulating factor in patients with acute myelogenous leukemia (AML). Twenty patients received myeloablative chemotherapy or chemo-radiotherapy including total body irradiation followed by the infusion of PBSC. PBSC were collected by large-volume leukaphereses. The mean number of mononuclear cells and CD34-positive cells infused were 7.2 x 10(8)/kg (range, 2.2-16.6), and 6.6 x 106/kg (range, 2.1-27.7), respectively. Engraftment failure was not seen in the enrolled patients. The median time to neutrophil (> or = 500/microL) and platelet recovery (> or = 50,000/microL) from the transplant was 12 days (range, 8-20) and 28 days (range, 10-600), respectively. The 2-year probability of disease-free survival (DFS) and relapse were 43% and 57% for patients with AML transplanted in first complete remission (CR1). The outcome of the patients transplanted in the advanced status was significantly worse than the patients transplanted in CR1 (P=0.04). Most relapses occurred within 1 year after transplantation. Fatal hepatic veno-occlusive disease was observed in one case. Other transplantation-related toxicities were mild. Our results demonstrated that autologous transplantation of high-dose consolidation chemotherapy-mobilized peripheral blood progenitor cells is feasible in the patients with AML in CR1. To further reduce the risk of leukemia relapse, much effort should be contributed to the field of ex vivo purging and post-transplant immunotherapy.

Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of a combination chemotherapy consisting of idarubicin, cytarabine, and topotecan. Twenty-seven patients were treated: four with primary refractory AML, nine with AML in first relapse, four with AML in second relapse, and 10 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1-3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1-5, and topotecan 1.25 mg/m(2) over 24 hr on days 1-5. Median age was 42 years (range 17-65 years). All patients were evaluable for response: 14 (51.9%) achieved complete remission, 10 with AML (59%) and four with MDS (40%), respectively. Thirteen AML patients (excluding four relapsed after autologous stem cell transplantation) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1-2 years and receiving S1; group 3, first CR duration 0-1 years and receiving S1; and group 4, first CR duration 0-1 years and receiving S2, S3, or S4 after failing S1. The response rate of each group was as follows: group 1, one of two (50%); group 2, one of one (100%); group 3, four of four (100%); group 4, two of six (33.3%). The median remission duration and survival of patients with AML were six and 12 months, respectively. Median duration of survival in 10 MDS patients was 15 months, and all four MDS patients achieving a CR maintained continuous CR with a median follow-up of 11 months. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 89% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 22 days (11-34) and for platelets > 20 x 10(9)/l 35 days (11-58). Reversible grade 3-4 toxicities included diarrhea (two patients) and mucositis (seven patients). We conclude that combination chemotherapy with intermediate dose cytarabine, idarubicin, and topotecan has significant antileukemic activity and acceptable toxicity in salvage AML and high-risk MDS.

Mitochondrial gene transfer ribonucleic acid (tRNA)Leu(UUR) 3243 and tRNA(Lys) 8344 mutations and diabetes mellitus in Korea.

The high prevalence of diabetic patients with a mutation in the mitochondrial gene (the 3243 and 8344 bp mutations) has been identified in Japan. To determine the prevalence of diabetic patients with those mutations in Korea, we randomly screened selected 503 clinical diabetic patients regardless of their diabetes types. We found only 1 patient with the mitochondrial DNA mutation at position 3243 (percent mutation, 32%), and the mitochondrial DNA mutation at position 8344 was not found in any of the patients. The affected subject was a 22-yr-old man with a history of myoclonic epilepsy and mild sensorineural hearing loss, a 1-yr duration of diabetes mellitus, and a low level C peptide response to oral glucose. Because of the low frequency of these mutations in the Korean diabetic population, we concluded that these particular mutations of mitochondrial DNA may not be a common contributor to diabetes mellitus in Korea.