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.
Highlights
Hematopoiesis involves a hierarchy of hematopoietic stem cells (HSC), hematopoietic progenitor cells (HPC), and mature blood cells
Ectopic Myc expression was shown earlier to suffice to induce a myeloid disorder with features of myeloproliferation/ acute myeloid leukemia [25]
We hypothesized that a Myc-driven hematopoietic cancer/ pre-cancer model could serve as a tool for investigating changes in the microenvironment that could be induced by the cancer cell-intrinsic oncoprotein
Summary
Hematopoiesis involves a hierarchy of hematopoietic stem cells (HSC), hematopoietic progenitor cells (HPC), and mature blood cells. Since the vast majority of HSC are in a quiescent state, the regulation of their entry into the G1 and S phase in response to demand is a crucial step in hematopoiesis. This checkpoint is frequently inactivated in blood cancers and contributes to uncontrolled proliferation of the malignant clone [1,2,3]. E. g., members of the wingless (Wnt) - frizzled (Fzd) pathway play an important role in the regulation of HSC self-renewal and differentiation. C-Myc (Myc) has been shown to play an essential role in regulating the balance between self-renewal and differentiation of HSCs, most probably by altering HSC-microenvironment interactions [10] About 15 % of all genes are regulated by Myc family members [7], and Myc proteins (c-Myc, N-Myc, and L-Myc) are overexpressed in at least 70 % of all aggressive human cancers [8, 9]. c-Myc (Myc) has been shown to play an essential role in regulating the balance between self-renewal and differentiation of HSCs, most probably by altering HSC-microenvironment interactions [10]
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