Oncotarget

Priority Research Papers:

In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment

Katharina Franke, Baiba Vilne, Olivia Prazeres da Costa, Martina Rudelius, Christian Peschel, Robert A.J. Oostendorp and Ulrich Keller _

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Oncotarget. 2015; 6:21827-21839. https://doi.org/10.18632/oncotarget.5217

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Abstract

Katharina Franke1, Baiba Vilne2, Olivia Prazeres da Costa3, Martina Rudelius4, Christian Peschel1,5, Robert A.J. Oostendorp1 and Ulrich Keller1,5

1 III. Medical Department, Technische Universität München, Munich, Germany

2 German Heart Center Munich, Experiential Cardiology, Technische Universität München, Munich, Germany

3 Institute for Medical Microbiology, Immunology and Hygiene (MIH), Technische Universität München, Munich, Germany

4 Institute of Pathology, Universität Würzburg and Comprehensive Cancer Center Mainfranken, Germany

5 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Ulrich Keller, email:

Keywords: Myc, leukemia, microenvironment, endothelial cells

Received: May 21, 2015 Accepted: July 26, 2015 Published: August 19, 2015

Abstract

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.


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