EP300-ZNF384 Rearrangement Drive B-Cell Acute Lymphoblastic Leukemia Development By Activating IL3-IL3RA Signaling

Abstract

Abstract: EP300-ZNF384 chromosome rearrangement serves as an oncogenic driver in B-cell acute lymphoblastic leukemia development. However, the oncogenic mechanisms underlying EP300-ZNF384 remain largely elusive. Recent evidence shows that the gene expression signature in EP300-ZNF384-positive patients enriched in cytokine-cytokine receptor and JAK-STAT signaling. We reason the correlated cytokine-cytokine receptor and JAK-STAT signaling might play important roles in EP300-ZNF384 fusion primed B-cell acute lymphoblastic leukemia. To investigate this concept, we identified EP300-ZNF384 substantially induces the expression of IL3RA on cell membranes of B lineage cells. Further, we proved IL3 supplement promotes EP300-ZNF348 positive cells proliferation and colony formation by activating JAK-STAT signaling. IL3RA knockdown reduces the responsiveness of EP300-ZF384 positive cells to IL3 stimulation. Dual luciferase assay and ChIP-qPCR assay confirm that EP300-ZNF384 binds the promoter region of IL3RA and actives its transcription. Interestingly, IL3 expression was significantly upregulated in ZNF384 rearranged B-cell acute lymphoblastic leukemia patients comparing with B others through analyzing bioinformatics databases. These findings underscore the critical role of IL3-IL3RA signaling under EP300-ZNF384 driven B-cell acute lymphoblastic leukemia and imply EP300-ZNF384 positive patients might benefit from JAK inhibitors. Keywords: EP300-ZNF384, B-cell Acute Lymphoblastic leukemia, IL3RA, IL3 JAK, STAT