melphalan and Precancerous-Conditions

We used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells (B cells, normal plasma cells, monoclonal gammopathy of undetermined significance [MGUS], presentation myeloma, and plasma cell leukemia). We show that methylation patterns in these cell types are capable of distinguishing nonmalignant from malignant cells and the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to plasma cell leukemia with remethylation of the genome, particularly of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples, which was associated with cytogenetic differences between samples. More specifically, we found methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the greatest impact on DNA methylation. Two groups of hyperdiploid samples were identified, on the basis of unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation changes significantly during disease progression and between cytogenetic subgroups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cluster Analysis; Cyclophosphamide; Dexamethasone; Disease Progression; DNA Methylation; Doxorubicin; Humans; In Situ Hybridization, Fluorescence; Melphalan; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Precancerous Conditions; Prednisolone; Prognosis; Stem Cell Transplantation; Thalidomide; Vincristine

Melphalan (L-phenylalanine mustard), a cytostatic drug used in treatment of human breast cancer, was injected into mice bearing preneoplastic hyperplastic alveolar nodule mammary outgrowth line D2. Melphalan, doses of either 2.5 or 5.0 mg/kg, markedly enhanced tumor formation in its mammary nodule outgrowth line. Samples of nodule outgrowths in untreated mice produced 13% tumors by 9 months after transplantation, whereas nodule outgrowths in melphalan-treated mice produced 57 and 85% mammary tumors in the lower and higher dose groups, respectively.

Topics: Animals; Carcinogens; Female; Humans; Hyperplasia; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Precancerous Conditions; Stimulation, Chemical

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Female; Fluorouracil; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Mice, Inbred BALB C; Precancerous Conditions; Prednisone; Vincristine

Topics: Anemia, Sideroblastic; Bone Marrow Examination; Cytarabine; Female; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulins; Iron; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Mercaptopurine; Middle Aged; Multiple Myeloma; Muramidase; Precancerous Conditions; Prednisone; Staining and Labeling; Vincristine