Priority Research Papers:
An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells
Metrics: PDF 775 views | HTML 1886 views | ?
Sayyed K. Zaidi1, Andrew W. Perez1, Elizabeth S. White1, Jane B. Lian1, Janet L. Stein1 and Gary S. Stein
1 Department of Biochemistry and University of Vermont Cancer Center, The University of Vermont Larner College of Medicine, Burlington, VT, USA
Sayyed K. Zaidi, email:
Keywords: RUNX, leukemia, miR-29, AML1-ETO, t(8;21)
Received: April 18, 2017 Accepted: April 24, 2017 Published: May 24, 2017
Acute myeloid leukemia (AML) is characterized by an aggressive clinical course and frequent cytogenetic abnormalities that include specific chromosomal translocations. The 8;21 chromosomal rearrangement disrupts the key hematopoietic RUNX1 transcription factor, and contributes to leukemia through recruitment of co-repressor complexes to RUNX1 target genes, altered subnuclear localization, and deregulation of the myeloid gene regulatory program. However, a role of non-coding microRNAs (miRs) in t(8;21)-mediated leukemogenesis is minimally understood. We present evidence of an interplay between the tumor suppressor miR-29b-1 and the AML1-ETO (also designated RUNX1-RUNX1T1) oncogene that is encoded by the t(8;21). We find that AML1-ETO and corepressor NCoR co-occupy the miR-29a/b-1 locus and downregulate its expression in leukemia cells. Conversely, re-introduction of miR-29b-1 in leukemia cells expressing AML1-ETO causes significant downregulation at the protein level through direct targeting of the 3’ untranslated region of the chimeric transcript. Restoration of miR-29b-1 expression in leukemia cells results in decreased cell growth and increased apoptosis. The AML1-ETO-dependent differentiation block and transcriptional program are partially reversed by miR-29b-1. Our findings establish a novel regulatory circuit between the tumor-suppressive miR-29b-1 and the oncogenic AML1-ETO that controls the leukemic phenotype in t(8;21)-carrying acute myeloid leukemia.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.