C/EBPα-Induced MicroRNA 30c Inactivates Notch1 During Granulopoiesis and Is Downregulated In Acute Myeloid Leukemia

Abstract

Abstract 2368The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPα) is crucial for normal granulopoiesis and frequently disrupted in acute myeloid leukemia (AML). Loss of expression or function of C/EBPα leads to a block of myeloid differentiation. MicroRNAs inhibiting translation of mRNA into protein were identified as critical players in stem cell development. We and others have already shown that C/EBPα exerts its effects by regulating microRNAs such as miR-223 and miR-34a. In a global microRNA-array screen we found miR-30c as a novel target of C/EBPα during granulocytic differentiation. Wild-type C/EBPα-p42 upregulates miR-30c expression, whereas the C/EBPα-p30 mutant, found in AML, does not. Furthermore, G-CSF upregulates miR-30c expression during granulocytic differentiation of primary human CD34-positive progenitor cells. C/EBPα induces miR-30c and downregulates Notch1, a putative target of miR-30c, on protein, but not mRNA level. A block of miR-30c by LNAs prevents C/EBPα–induced downregulation of Notch1 protein expression. miR-30c is a tumor suppressor and downregulated in various subtypes of AML. In mice, miR-30c shows a high expression in LSK (including hematopoietic stem cells), GMP (granulocytic monocytic precursors) and granulocytes. An induced knock-out of C/EBPα in mice leads to a significantly downregulation of miR-30c expression in bone marrow cells. Our data indicates that C/EBPα-induced miR-30c inactivates Notch1 during granulopoiesis and is downregulated in AML. These data reveal the importance of deregulated microRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML. Disclosures:No relevant conflicts of interest to declare.