cyclin-d1 and Leukemia--Plasma-Cell

The IGH/CCND1 fusion gene has been reported in many hematologic tumors such as mantle cell lymphoma, chronic lymphocytic leukemia, prolymphocytic leukemia, multiple myeloma, and plasma cell leukemia. We report a case of plasma cell leukemia showing five IGH/CCND1 fusion signals by interphase fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis and multicolor spectral karyotyping showed a complex karyotype that did not include t(11;14). Metaphase FISH studies revealed three IGH/CCND1 fusion signals, two of which were amplified signals. These findings indicate that IGH/CCND1 fusion gene was amplified and interspersed in several chromosomes. The patient was treated with intensive chemotherapy. However, the clinical course was very aggressive. The amplification of the IGH/CCND1 fusion gene may contribute to the aggressive course of the disease. To our knowledge, this is the first case showing amplification of the IGH/CCND1 gene in plasma cell neoplasms.

Topics: Cyclin D1; Humans; Immunoglobulin Heavy Chains; In Situ Hybridization, Fluorescence; Leukemia, Plasma Cell; Male; Middle Aged; Spectral Karyotyping

The retinoblastoma protein (pRb), p16(INK4A), D-type cyclins, and their partners cyclin-dependent kinase (CDK) 4 and 6 constitute a G(1) regulatory pathway commonly targeted in tumorigenesis. Several malignancies show a reciprocal correlation between genetic alterations of single members of the pRb pathway. Therefore, we determined the frequency of Rb deletions and cyclin D1 alterations by fluorescence in situ hybridization as well as 5' CpG island hypermethylation of the p16(INK4A)gene using methylation-specific polymerase chain reaction in bone marrow mononuclear cells from 82 individuals with plasma cell disorders. Alterations in at least one of the components of the pathway were found in 75%. Cyclin D1 translocations or amplifications were detected in 14/82 (17.1%), Rb deletions at 13q14 in 23/82 (28%) of the cases, including three (3.6%) homozygous deletions. p16(INK4A) was hypermethylated in 33/57 (57.9%) of the samples. Further analysis revealed a highly significant correlation between cyclin D1 alterations and extramedullar or leukemic myeloma manifestations (P = 0.014; Fisher's test). Whereas Rb deletions seemed to occur alternatively to cyclin D1 alterations, no reciprocal correlation was found between p16(INK4A) hypermethylations and cyclin D1 or Rb locus aberrations. Cyclin D1 locus alterations and Rb deletions were associated with a significantly worse prognosis whereas p16(INK4A) hypermethylation had no impact on survival. We conclude that cyclin D1 and Rb aberrations seem to occur as alternative events in plasma cell malignancies and contribute to clinical course and prognosis. In contrast, although p16(INK4A) hypermethylation is frequent, inactivation of p16(INK4A) seems not to be involved in the pathogenesis of plasma cell disorders.

Topics: Chromosome Aberrations; Chromosome Mapping; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 14; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Deletion; Humans; Immunoglobulins; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Retinoblastoma Protein; Survival Rate; Translocation, Genetic

We analysed PRAD1/cyclin D1 expression in 20 patients with plasma cell malignancy by Northern analysis. 6/17 multiple myeloma patients and 3/3 plasma cell leukaemia patients showed PRAD1/cyclin D1 expression. This incidence appeared to be higher than the expected incidence based on previous studies. Southern analysis did not show rearrangement of the bcl-1 region. Although there was no statistical difference, the PRAD1/cyclin D1 negative group showed a 1-year survival of 81.8%, 3-year survival of 45.5% and 5-year survival of 22.7%, and those for the PRAD1/cyclin D1 positive group were 63.5%, 16.9% and 16.9%, respectively. Further study is required to determine whether PRAD1/cyclin D1 expression is a prognostic factor.

Topics: Aged; Blotting, Southern; Cyclin D1; Female; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Prognosis; Survival Analysis

Two patients with plasma cell leukemia (PCL) with a t(11;14)(q13;q32) translocation are reported. Case 1 is a 64-year-old woman diagnosed as having primary PCL (IgA/lambda, Stage III) with high serum LDH and beta 2-microglobulin (beta 2MG) levels. She was treated with combination chemotherapy but died of gastrointestinal bleeding on the 45th hospital day. Case 2 is a 52-year-old man, initially diagnosed with multiple myeloma (IgG/kappa, Stage III) in August 1993. Relapse several months after primary chemotherapy was characterized by a rapid increase in plasma cells in peripheral blood, high serum LDH and beta 2MG levels, and resistance to further chemotherapy. Both cases showed complex karyotypic abnormalities including t(11;14), and Northern analysis revealed overexpression of the PRAD1/ cyclin D1 gene. The PRAD1 gene is found on chromosome band 11q13 and encodes cyclin D1. Cyclin D1 plays an important role in control of the cell cycle, and overexpression of PRAD1/cyclin D1 may be involved in disease progression in these cases.

Topics: Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Cyclins; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Oncogene Proteins; Translocation, Genetic

In this study, we analyzed 69 plasma cell neoplasms, including 54 multiple myelomas (MMs), 3 cases of plasma cell leukemia, and 12 plasmacytomas, for expression of cyclin D1 protein using an immuno-histochemical method applied to routinely fixed, paraffin-embedded tissue sections. Cyclin D1 was expressed in 18 (26%) of 69 plasma cell neoplasms, including 16 (30%) of 54 MMs and 2 (17%) of 12 plasmacytomas. Three cases of plasma cell leukemia were negative. Cyclin D1 expression correlated with the cytologic differentiation and histologic stage of MM. Twelve (75%) of 16 MMs had intermediate or immature cytologic features and were histologic Stage III. With use of a polymerase chain reaction assay, we also analyzed six cases (three cyclin D1 positive, three cyclin D1 negative) for the t(11;14); one MM carried the t(11;14) and expressed cyclin D1 protein. We conclude that cyclin D1 expression occurs in approximately one-quarter of plasma cell neoplasms and correlates with the degree of cytologic differentiation and histologic stage. The relatively high frequency of cyclin D1 expression, compared with the less than 5% incidence of the t(11;14) detected by conventional cytogenetics reported in the literature, suggests that upregulation of cyclin D1 protein might be the result of mechanisms other than the t(11;14).

Topics: Adult; Aged; Aged, 80 and over; Cyclin D1; Female; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Immunohistochemistry; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Paraffin Embedding; Plasmacytoma; Polymerase Chain Reaction; Survival Rate

Topics: Aged; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Chronic Disease; Cyclin D1; Female; Humans; Leukemia, Plasma Cell; Translocation, Genetic