Abstract
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.
Highlights
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia
MicroRNAs, a class of small non-coding RNAs, are important regulators of normal haematopoiesis and leukemia development[13]. They bind to the 3′ untranslated region (3′UTR) of target messenger RNAs through an imperfect match, which leads to mRNA destabilization and/or translational inhibition[14]
Since it was shown to be oncogenic in several solid tumors[29, 30] and rarely studied in Acute myeloid leukemia (AML), we focused further investigations on miR-182
Summary
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. MiR-182 expression is highly elevated in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. CEBPA encodes the myeloid transcription factor C/EBPα, a master regulator of granulopoiesis[4]. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of normal haematopoiesis and leukemia development[13]. They bind to the 3′ untranslated region (3′UTR) of target messenger RNAs (mRNAs) through an imperfect match, which leads to mRNA destabilization and/or translational inhibition[14]. The importance of C/EBPα-mediated suppression of oncogenic miRNAs in promoting myelopoiesis has not been shown
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