PML-RARα Repressed Microrna 126 Mediates Differentiation in Acute Promyelocytic Leukemia By Targeting the Protooncogene C-Myb

Almost one tenth of acute myeloid leukemias (AML) are related to t(15;17) translocation. This aberration leads to the PML-RARα fusion protein, which causes a transcriptional block of differentiation and could be resolved by all-trans-retinoic acid (ATRA). MicroRNAs (miRs) are small noncoding RNAs which are ascribed to be important regulators of cell proliferation, development, differentiation and apoptosis. MiR-126 is regarded as tumor suppressor in diverse tissues, but relatively little is known about its functional role in normal and malignant hematopoiesis. In this report, we reveal that oncogenic PML-RARα fusion protein is a repressor of miR-126 expression. Thus, we could demonstrate a significant downregulation of miR-126 expression in presence of the PML-RARα fusion protein in APL versus other AML patient samples and in a PML-RARα Knock in mouse model. We further show that ATRA induced differentiation of APL cell line NB4 comes along with an increase of miR-126 expression. The transient overexpression of miR-126 enhances ATRA stimulated differentiation of myeloid cells, whereas the opposite effect was noticed when endogenous expression of miR-126 was knocked down. Most interestingly, we observed a significant upregulation of miR-126 expression in APL blasts during ATRA treatment of APL patients. C-Myb proto-oncogene was found to be a putative target of miR-126 by analysing the 3’UTR. We could show a reduced c-Myb protein level after enforced expression of miR-126. Further, we reveal that miR-126 leads to a posttransciptional downregulation of c-Myb expression by directly targeting its 3`UTR. Our data suggest miR-126 as an important regulator of differentiation in acute promyelocytic leukemia, targeting the proto-oncogene c-Myb and recommend microRNAs to be potential therapeutic agents.