CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network

This is the authors' abstract. We don't add key points for this paper.

CBFA2T3-GLIS2 is a fusion oncogene found in pediatric acute megakaryoblastic leukemia that is associated with a poor prognosis. We establish a model of CBFA2T3-GLIS2 driven acute megakaryoblastic leukemia that allows the distinction of fusion specific changes from those that reflect the megakaryoblast lineage of this leukemia. Using this model, we map fusion genome wide binding that in turn imparts the characteristic transcriptional signature. A network of transcription factor genes bound and upregulated by the fusion are found to have downstream effects that result in dysregulated signaling of developmental pathways including NOTCH, Hedgehog, TGFβ, and WNT. Transcriptional regulation is mediated by homo-dimerization and binding of the ETO transcription factor through the nervy homology region 2. Loss of nerve homology region 2 abrogated the development of leukemia, leading to downregulation of JAK/STAT, Hedgehog, and NOTCH transcriptional signatures. These data contribute to the understanding of CBFA2T3-GLIS2 mediated leukemogenesis and identify potential therapeutic vulnerabilities for future studies. CBFA2T3-GLIS2 is a fusion oncogene found in a subset of pediatric acute megakaryoblastic leukemia associated with a poor prognosis. Here, Garfinkle et al. map the gene regulatory network of CBFA2T3-GLIS2 using a humanized murine model and identify signaling pathways required for leukemogenesis.