MicroRNA let-7b downregulates AML1-ETO oncogene expression in t(8;21) AML by targeting its 3'UTR

Daniel T Johnson; Amanda G Davis; Jie-Hua Zhou; Edward D Ball; Dong-Er Zhang

doi:10.1186/s40164-021-00204-7

MicroRNA let-7b downregulates AML1-ETO oncogene expression in t(8;21) AML by targeting its 3'UTR

Exp Hematol Oncol. 2021 Feb 2;10(1):8. doi: 10.1186/s40164-021-00204-7.

Authors

Daniel T Johnson^{1

2

3}, Amanda G Davis^{1

2

3}, Jie-Hua Zhou^{1

4}, Edward D Ball^{1

4}, Dong-Er Zhang^{5

6

7

8}

Affiliations

¹ Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA.
² Biological Sciences Graduate Program, University of California San Diego, La Jolla, San Diego, CA, USA.
³ Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA, USA.
⁴ BMT Division, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.
⁵ Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA. dez@ucsd.edu.
⁶ Biological Sciences Graduate Program, University of California San Diego, La Jolla, San Diego, CA, USA. dez@ucsd.edu.
⁷ Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA, USA. dez@ucsd.edu.
⁸ Department of Pathology, University of California San Diego, La Jolla, San Diego, CA, USA. dez@ucsd.edu.

Abstract

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.

Keywords: AML1-ETO (RUNX1-RUNX1T1); let-7; miRNA; t(8;21) acute myeloid leukemia.

Abstract

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