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Background  Acute myeloid leukemia (AML) with the t(8;21)(q22;q22) chromosomal translocation is among the most common subtypes of AML and produces the  AML1-ETO  ( RUNX1-ETO ,  RUNX1-RUNX1T1 ) oncogenic fusion gene. AML1-ETO functions as an aberrant transcription factor which plays a key role in blocking normal hematopoiesis. Thus, the expression of AML1-ETO is critical to t(8;21) AML leukemogenesis and maintenance. Post-transcriptional regulation of gene expression is often mediated through interactions between  trans -factors and  cis -elements within transcript 3′-untranslated regions (UTR).  AML1-ETO  uses the 3′UTR of the  ETO  gene, which is not normally expressed in hematopoietic cells. Therefore, the mechanisms regulating AML1-ETO expression via the 3’UTR are attractive therapeutic targets.    Methods  We used RNA-sequencing of t(8;21) patients and cell lines to examine the 3′UTR isoforms used by  AML1-ETO  transcripts. Using luciferase assay approaches, we test the relative contribution of 3′UTR  cis  elements to AML1-ETO expression. We further use let-7b microRNA mimics and anti-let-7b sponges for functional studies of t(8;21) AML cell lines.    Results  In this study, we examine the regulation of AML1-ETO via the 3’UTR. We demonstrate that  AML1 - ETO  transcripts primarily use a 3.7 kb isoform of the  ETO  3′UTR in both t(8;21) patients and cell lines. We identify a negative regulatory element within the  AML1-ETO  3′UTR. We further demonstrate that the let-7b microRNA directly represses AML1-ETO through this site. Finally, we find that let-7b inhibits the proliferation of t(8;21) AML cell lines, rescues expression of AML1-ETO target genes, and promotes differentiation.    Conclusions  AML1-ETO is post-transcriptionally regulated by let-7b, which contributes to the leukemic phenotype of t(8;21) AML and may be important for t(8;21) leukemogenesis and maintenance.

MicroRNA let-7b downregulates AML1-ETO oncogene expression in t(8;21) AML by targeting its 3′UTR