Data from Oncogenic <i>Kras<sup>G12D</sup></i> Activation in the Nonhematopoietic Bone Marrow Microenvironment Causes Myelodysplastic Syndrome in Mice

Abstract

<div>Abstract<p>The bone marrow microenvironment (BMME) is key player in regulation and maintenance of hematopoiesis. Oncogenic <i>RAS</i> mutations, causing constitutive activation of multiple tumor-promoting pathways, are frequently found in human cancer. So far in hematologic malignancies, <i>RAS</i> mutations have only been reported to occur in hematopoietic cells. In this study, we investigated the effect of oncogenic <i>Kras</i> expression in the BMME in a chimeric mouse model. We observed that an activating mutation of <i>Kras</i> in the nonhematopoietic system leads to a phenotype resembling myelodysplastic syndrome (MDS) characterized by peripheral cytopenia, marked dysplasia within the myeloid lineage as well as impaired proliferation and differentiation capacity of hematopoietic stem and progenitor cells. The phenotypic changes could be reverted when the BM was re-isolated and transferred into healthy recipients, indicating that the <i>Kras<sup>G12D</sup></i>-activation in the nonhematopoietic BMME was essential for the MDS phenotype. Gene expression analysis of sorted nonhematopoietic BM niche cells from <i>Kras<sup>G12D</sup></i> mice revealed upregulation of multiple inflammation-related genes including IL1-superfamily members (<i>Il1α, Il1β, Il1f9</i>) and the NLPR3 inflammasome. Thus, pro-inflammatory IL1-signaling in the BMME may contribute to MDS development. Our findings show that a single genetic change in the nonhematopoietic BMME can cause an MDS phenotype. Oncogenic <i>Kras</i> activation leads to pro-inflammatory signaling in the BMME which impairs HSPCs function.</p>Implications:<p>These findings may help to identify new therapeutic targets for MDS.</p></div>