Idh1 mutasyonunun gliom oluşumunun erken aşamalarında monosit farklılaşmasına etkilerinin transkriptom düzeyinde karakterizasyonu

Gliomas are the most common primary brain tumors with a distinct histological and genomic background. IDH mutations are the most common genetic alteration in lower grade gliomas and almost always effect the same residue (R132H) that confer new function to the IDH enzyme. IDH1 R132H produces an oncometabolite namely 2-hydroxygluterate (2-HG) and its accumulation leads to genome wide epigenetic changes. In addition to its cell intrinsic roles in tumor initiation, 2-HG have been proposed to effect the tumor microenvironment acting in a paracrine manner. In this study, we aimed to investigate the effects of secreted factors from astrocytes that mimic the early stages of IDH1 R132H gliomas on monocyte differentiation. To this end immortal human astrocytes that express IDH1 R132H in a doxycycline-inducible manner were used to mimic tumor initiation and conditioned media (CM) were collected in different time points and primary monocytes were exposed to it during differentiation to macrophages. Transcriptome wide analysis of differentiated macrophages by RNA sequencing reveal that 124 genes are differentially expressed in response to IDH1 mutation. Gene ontology analysis indicating that IDH1 mutation may interfere with p53 signaling pathway. In consistent with the literature, negative regulation of complement activation signatures elevated in IDH1 R132H exposed time point cases. Th1 and Th2 cell differentiation, cytotoxic T cell homeostasis are the other significantly enriched pathways in given genes of interest. It has been speculated that secreted factors from astrocytes in early stages of glioma formation may affect the macrophages resulting transcriptomic changes to shape tumor microenvironment.