CBFA2T3-GLIS2 Mediates Transcriptional Regulation of Developmental Pathways through a Gene Regulatory Network

CBFA2T3-GLIS2 is a fusion oncogene found in pediatric acute megakaryoblastic leukemia (AMKL) that is associated with a poor prognosis. We established a model of CBFA2T3-GLIS2 driven AMKL that allows the distinction of fusion specific changes from those that reflect the megakaryoblast lineage of this leukemia. Using this model, we mapped genome wide binding that in turn imparts the characteristic transcriptional signature. A network of transcription factor genes bound and upregulated by the fusion were found to have downstream effects that result in dysregulated signaling of developmental pathways including NOTCH, Hedgehog, TGF, and WNT. Transcriptional regulation is mediated by homo-dimerization and binding of the ETO transcription factor through the nervy homology region 2 (NHR2). Loss of NHR2 abrogated the development of leukemia and led to the downregulation of JAK/STAT and NOTCH transcriptional signatures. These data contribute to the understanding of CBFA2T3-GLIS2 mediated leukemogenesis and identify potential therapeutic vulnerabilities for future studies.