Both p16 and p15, encoded by the genes located on chromosome 9p21, are inhibitors of cyclin-dependent kinases (CDK4/6) and the upstream regulators of Rb function. In hematopoietic malignancies, deletion of p16/p15 locus has been shown to be highly specific to lymphoid, and more particularly from B-lineage malignancies except multiple myeloma (MM). To investigate whether these genes are inactivated by deletions, mutations, and hypermethylation of the 5′ CpG islands, we examined 12 MM patients by Southern hybridization and polymerase chain reaction–single-strand conformation polymorphism (PCR-SSCP) analysis. No deletions nor mutations of the p16 and p15 genes were found. However, hypermethylation was observed in 75% for p16 and 67% for p15 in our group of MM patients. Such high frequencies of involvement of these genes in MM make them hitherto the most common genetic abnormalities in this disease. Concomitant hypermethylation, uncommon thus far in the literature of the study of these genes, is a rather common phenomenon, occurring in 67% of our patient group. Moreover, hypermethylation of p16/p15 was associated with blastic disease and concomitant hypermethylation of both genes may be pathogenetically related to plasmacytoma development. These results indicate that these genes are important in MM pathogenesis. Here we report, for the first time in the literature, the high incidences of p16 and p15 alterations in MM, not by homozygous deletions or mutations, but solely by hypermethylation of the 5′ CpG islands, which may be a specific mechanism in this disease.
To gain insight into the real incidence of the numeric chromosomal aberrations and the cell lineage involvement of the neoplastic process in multiple myeloma (MM) , we examined 18 Chinese MM patients by May-Grunwald-Giemsa (MGG) staining and fluorescence in situ hybridization using three DNA centromeric probes specific for chromosomes 3 , 7 , and 9. In this investigation , cytogenetic abnormalities were detected in plasma cells (PCs) , myeloid cells (MCs), and lymphoid cells (LCs) in all of the MM patients studied. This is the first demonstration of the cytogenetic aberration involved in the myeloid series. Multiple myeloma (MM) has been regarded as the neoplastic disease of the terminally differentiated B cell with elusive oncogenesis. Although the majority of the tumor cells found in the bone marrow can be recognized by their typical plasma cell morphology, they are the progeny of a yet unidentified myeloma progenitor cell. Suggested possibilities of this clonogenic cell include peripheral blood B-lymphoid cell, pre-B cell, and hematopoietic stem cell.1 Thus far, knowledge on the nature and development of the clonogenic cell has been lacking. This shortcoming has been an obstacle to rational intervention and contributed to a high fatality of MM from ineffective treatment.The low proliferative rate of the tumor cells in this malignancy has hampered the conventional cytogenetic analysis. An abnormal karyotype, often a complex mixture of numeric and structural changes, is found in ϳ50% of patients.2 Recent data have revealed that 55% of MM patients had three or more trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. 3 The significance of these chromosomal aberrations in MM pathogenesis remains obscure. As a large number of proliferating or nondividing cells can be examined, use of fluorescence in situ hybridization (FISH) has improved the detection of cytogenetic abnormalities in MM. In addition, by combination with morphological assessment of the cells studied, the lineage of cells that are involved in the neoplastic transformation can be elucidated. Using FISH and 10 ␣-satellite DNA probes, Drach et al 4 showed that 88.9% of MMs were aneuploid for at least one chromosome examined and 66% had aberrations in three or more chromosomes. In the same study, mature myeloid cells evaluated showed no abnormality. 4 After FISH procedure, cytomorphological details are so obscured that it would be very difficult to ascertain the cell types being assessed. Using combined morphological and FISH
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