Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF-1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress.

Osteolysis and hypercalcemia are observed in 5-15%, and 10%, respectively, of malignant lymphoma patients during their clinical course. However, both osteolysis and hypercalcemia are uncommon at onset of the disease. We encountered a 24-year-old male non-Hodgkin's lymphoma patient who had multiple osteolytic lesion from the onset of the disease and repeated episodes of hypercalcemia during the clinical course. The patient died with refractory disease. We studied the expression of chemokines which might affect bone resorption using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Increased expressions of MIP-1alpha, MIP-1beta and RANKL, which are osteoclast-activating factors, were observed in the RNA derived from the patient's lymphoma cells. The secretion of osteoclast-activating factors such as MIP-1alpha by the tumor cells (and/or bone marrow stromal cells) might be involved in the etiology of osteolysis and hypercalcemia in some malignant lymphoma cases.

Abstract. Chronic myelogenous leukemia (CML) has a typical progressive course with transition from a chronic phase to a terminal blast crisis phase. The mechanisms that lead to disease progression remain to be elucidated. To understand the role of aberrant methylation in the progression of CML, DNA methylation patterns in 16 patients with CML blast crisis were analyzed. Methylation status was analyzed by methylationspecific PCR (MSP) for 13 genes, including cell cycle regulating genes, DNA repair genes, apoptosis-related genes, a differentiation-associated gene and a cytokine signaling gene. The frequency of samples with methylation in each of the following genes were: p15, 18%; MGMT, 12%; RARβ, 12%; p16, 6%; DAPK, 6% and FHIT, 6%. In total, four (25%) cases showed methylation of at least one gene. None of the 16 cases showed hypermethylation of the hMLH1 or hMSH2 genes. These results suggest that hypermethylation of cell cycle control genes, but not DNA mismatch repair genes, play a significant role in the progression of CML. IntroductionChronic myelogenous leukemia (CML) has a typical progressive course with transition from the chronic phase to the terminal blast crisis phase. The mechanisms that lead to disease progression have yet to be elucidated. Cytogenetic and genetic changes occur in the majority of patients during disease progression. Approximately 70-80% of patients with CML blast crisis show additional chromosomal changes involving chromosomes 7, 8, 17, 19, 21 and 22, sometimes with duplication of the Ph chromosome (1). Genetic changes occurring in the progression to blast crisis include mutation of the p53 (20-30%), amplification of the c-myc (20%), deletion of the p16 (15%) and mutation of the Ras (6%) gene (2).DNA methylation at CpG sites in promoter regions is a frequent, acquired epigenetic event involved in the pathogenesis of various types of human malignancies. Methylation in the promoter region is capable of causing gene silencing, which may provide an alternative pathway to gene inactivation, in addition to deletions or mutations. The ABL1, calcitonin, ER and HIC1 genes were found to be frequently methylated in CML (3). Moreover, methylation of the ABL1 gene is associated with the progression of CML (4). These methylation phenotypes in CML provided a rationale for using demethylating agents such as 5-azacytidine and decitabine in a clinical setting, and preliminary clinical results were reported (3,5). To determine the role of aberrant methylation in the progression of CML, we analyzed DNA methylation patterns in CML blast crisis. Materials and methodsBone marrow cells were obtained from 16 patients who developed blast crisis during the follow-up of CML. Genomic DNA was extracted from low density mononuclear cells after the bone marrow cells were centrifuged in the presence of TRIzol reagent (Life Technologies Inc., Rockville, MD, USA). Control DNA was extracted from the peripheral blood of 10 healthy individuals. Methylation-specific PCR (MSP) was performed as previously described (6,7). B...

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In the rituximab era, several large studies have suggested that full-dose rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) might be the best treatment for patients with diffuse large B-cell lymphoma (DLBCL) aged 60 years and older. However, it remains unclear whether this is also the case for those aged 70 years and older. Previously untreated patients with DLBCL aged 70 years and older (elderly) were treated with R-70%CHOP, and patients younger than 70 years (younger) were treated with full-dose R-CHOP every 3 weeks, for a total of 6-8 cycles. Complete remission (CR) rates in elderly versus younger patients were 75 vs. 78% (p = 0.7), respectively. The 3-year overall survival, event-free survival and progression-free survival of elderly versus younger patients were 58 vs. 78% (p < 0.05), 45 vs. 70% (p < 0.05) and 64 vs. 72% (p = 0.43), respectively. Severe adverse events were more frequent in the elderly, even with the dose reduction in that age group. Three-year PFS with R-70%CHOP for patients aged 70 years and older was not significantly worse than that with full-dose R-CHOP for younger patients, suggesting that R-70% CHOP might be a reasonable choice for patients with DLBCL aged 70 years and older, especially for those with comorbidities.