TY  - JOUR
A1  - Franke, Katharina
A1  - Vilne, Baiba
A1  - da Costa, Olivia Prazeres
A1  - Rudelius, Martina
A1  - Peschel, Christian
A1  - Oostendorp, Robert A. J.
A1  - Keller, Ulrich
T1  - In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment
JF  - Oncotarget
N2  - Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45-Ter119-cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population.
KW  - stem-cells
KW  - mutations
KW  - C-Myc
KW  - Rho-GTPases
KW  - niche
KW  - leukemia
KW  - target
KW  - growth
KW  - cycle
KW  - apoptosis, Myc
KW  - microenvironment
KW  - endothelial cells
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145844
VL  - 6
IS  - 26
SP  - 21827
EP  - 21839
ER  - 
TY  - JOUR
A1  - Graf, Nicolas
A1  - Li, Zhoulei
A1  - Herrmann, Ken
A1  - Weh, Daniel
A1  - Aichler, Michaela
A1  - Slawska, Jolanta
A1  - Walch, Axel
A1  - Peschel, Christian
A1  - Schwaiger, Markus
A1  - Buck, Andreas K.
A1  - Dechow, Tobias
A1  - Keller, Ulrich
T1  - Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma
JF  - Oncotargets and Therapy
N2  - Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT). 
Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. 
Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. 
Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.
KW  - mammalian target of rapamycin
KW  - phosphatidylinositol-3-kinase
KW  - lymphoma
KW  - early response
KW  - NVP-BGT226
KW  - non-hodgkins-lymphoma
KW  - signaling pathway
KW  - FDG-PET
KW  - in-vivo
KW  - target
KW  - tumor
KW  - imaging proliferation
KW  - inhibition
KW  - positron emission tomography
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117915
VL  - 7
ER  -