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Pulikkan, J.A.* ; Peramangalam, P.S.* ; Dengler, V.* ; Ho, P.A.* ; Preudhomme, C.* ; Meshinchi, S.* ; Christopeit, M.* ; Nibourel, O.* ; Müller-Tidow, C.* ; Bohlander, S.K. ; Tenen, D.G.* ; Behre, G.*

C/EBPα-regulated microRNA-34a targets E2F3 during granulopoiesis and is downregulated in AML with CEBPA mutations.

Blood 116, 5638-5649 (2010)

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The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPα) is crucial for granulopoiesis and is deregulated by various mechanisms in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported in 10% of human patients with AML. Even though the C/EBPα-mutants are known to display distinct biological function during leukemogenesis, the molecular basis for this subtype of AML remains elusive. We have recently showed the significance of deregulation of C/EBPα regulated microRNA (miR) in AML. In this study, we report that miR-34a is a novel target of C/EBPα in granulopoiesis. During granulopoiesis miR-34a targets E2F3 and blocks myeloid cell proliferation. Analysis of AML samples with CEBPA mutations revealed a lower expression of miR-34a and elevated levels of E2F3 as well as E2F1, a transcriptional target of E2F3. Manipulation of miR-34a re-programmes granulocytic differentiation of AML blast cells with CEBPA mutations. These results define miR-34a as a novel therapeutic target in AML with CEBPA mutations.

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