Thomas Mohler

Publications (2)19.8 Total impact

• Source

  Available from: Jérôme Moreaux

  Article: Induction of angiogenesis by normal and malignant plasma cells.

  Dirk Hose, Jérôme Moreaux, Tobias Meissner, Anja Seckinger, Hartmut Goldschmidt, Axel Benner, Karène Mahtouk, Jens Hillengass, Thierry Rème, John De Vos, Michael Hundemer, Maud Condomines, Uta Bertsch, Jean-François Rossi, Anna Jauch, Bernard Klein, Thomas Möhler
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  ABSTRACT: Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
  Blood 04/2009; 114(1):128-43. · 9.90 Impact Factor
• Article: Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma.

  Dirk Hose, Thierry Rème, Tobias Meissner, Jérôme Moreaux, Anja Seckinger, Joe Lewis, Vladimir Benes, Axel Benner, Michael Hundemer, Thomas Hielscher, [......], Jens Hillengass, Uta Bertsch, Anna Jauch, John De Vos, Jean-François Rossi, Thomas Möhler, Jonathon Blake, Jürgen Zimmermann, Bernard Klein, Hartmut Goldschmidt
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  ABSTRACT: Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.
  Blood 02/2009; 113(18):4331-40. · 9.90 Impact Factor