Startpage Heidelberg University Hospital
Startpage Heidelberg University Hospital Institute of Human Genetics
Institute of Human Genetics
Institute of Human… Research Research in our… Research in our… Molecular Cytogenetics… Jauch A. /Boukamp… Multiple Myeloma

Reference Laboratory for Clinical Studies

Relevance of chromosomal and centrosomal aberrations for the prognosis and pathogenesis in multiple myeloma

Background: Multiple Myeloma (MM) is a malignant lymphoproliferative B-cell disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Besides established prognostic factors chromosomal aberrations are being discussed as prognostic parameters. In about 40% of MM, specific translocations can be detected, through which the oncogenes (CCND1, FGFR3, MAF etc) come under the control of enhancer elements of the immunoglobulin heavy chain (IgH) locus. In cases without such IGH translocations, numerical chromosome aberrations and hyperdiploid karyotypes are predominant. Recently, centrosome aberrations have been described as a possible cause of aneuploidy in hematological malignancies, which could also play a role in MM.

Goals: In this study, we prospectively evaluate the prognostic meaning of chromosome aberrations in MM, and we investigate centrosomal aberrations as a possible mechanism for the development of numerical aberrations.

Methods: We apply interphase-FISH on highly enriched CD138-positive bone marrow plasma cells using a comprehensive probe set to identify distinct subgroups of MM. Furthermore, we perform antibody staining against centrosomal proteins, and analyze the gene expression levels of centrosome-associated genes such as STK15, BUB1A, CCNB1, CDKN2A and CENPF.

Results: Using interphase-FISH we identified specific chromosome aberrations allowing a delineation of four distinct MM-subgroups: (1) a hyperdiploid subgroup with recurrent trisomies and a favorable risk profile, (2) a non-hyperdiploid subgroup with a t(4;14) frequently associated with deletion 13q14 and an aggressive course of disease, (3) patients with a t(11;14) and a better clinical outcome, and (4) a subgroup with gain of 1q21 associated with clinical parameters indicating a poor prognosis.

Collaborations:

PD Dr. med. Dipl-Phys Dirk Hose, Leiter des Labors für Myelomforschung,  Medizinische Klinik V, Universitätsklinikum Heidelberg.

Prof. Dr. med. Jens Hillengaß, Leiter der autologen Transplantations-Ambulanz,  Stellvertretender Leiter der Sektion Multiples Myelom, Leitung der Arbeitsgruppe "Hämatoonkologische Bildgebung", Medizinische Klinik V, Universitätsklinikum Heidelberg.

PD Dr. med. Marc-Steffen Raab, Leitung der Max-Eder Gruppe "Experimentelle Therapien hämatologischer Neoplasien" und der klinischen Arbeitsgruppe "Innovative Myelomtherapie",  Medizinische Klinik V, Universitätsklinikum Heidelberg.

  1. Neben K, Ott G, Schweizer S, Kalla J, Tews B, Katzenberger T, Hahn M, Rosenwald A, Ho AD, Müller-Hermelink HK, Lichter L, Krämer A. (2007). Expression of centrosome-associated gene products is linked to tetraploidization in mantle cell lymphoma. Int J Cancer, 120:1669-1677.
  2. Hensel M, Zoz M, Giesecke C, Benner A, Neben K, Jauch A, Stilgenbauer S, Ho AD, Krämer A. (2007). Centrosome aberrations correlate with cytogenetic and clinical risk profile and time to first treatment in B-cell chronic lymphocytic leukaemia. Int J Cancer, 121:978.983.
  3. Cremer FW, Kartal M, Hose D, Bila J, Buck I, Bellos F, Raab MS, Brough M, Moebus A, Hager HD, Goldschmidt H, Moos M, Bartram CR, Jauch A. (2005a). High incidence and intraclonal heterogeneity of chromosome 11 aberrations in patients with newly diagnosed multiple myeloma detected by multiprobe interphase FISH. Cancer Genet Cytogenet, 161:116-24.
  4. Cremer FW, Bila J, Buck I, Kartal M, Hose D, Ittrich C, Benner A, Raab MS, Theil AC, Moos M, Goldschmidt H, Bartram CR, Jauch A. (2005b). Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chromosomes Cancer, 44:194-203.
  5. Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, Pantesco V, DE Vos J, Jourdan E, Jauch A, Legouffe E, Moos M, Fiol G, Goldschmidt H, Rossi JF, Hose D, Klein B (2005). The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 106: 1021-1030
  6. Krämer A., Neben K, Ho AD. (2005). Centrosome aberrations in hematological malignancies. Cell Biol Int, 29:375-383.
  7. Neben K, Tews B, Wrobel G, Hahn M, Kokocinski F, Giesecke C, Krause U, Ho AD, Krämer A, Lichter P. (2004). Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes. Oncogene, 23: 2379-84.
  8. Neben K, Giesecke C, Schweizer S, Ho AD, Krämer A. (2003). Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile. Blood, 101:289-91.
  9. Krämer A, Schweizer S, Neben K, Giesecke C, Kalla J, Katzenberger T, Benner A, Muller-Hermelink HK, Ho AD, Ott G. (2003). Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin’s Lymphoma. Leukemia, 17:2207-2213.
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