An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells

作者：Zaidi Sayyed K; Perez Andrew W; White Elizabeth S; Lian Jane B; Stein Janet L; Stein Gary S

来源：Oncotarget, 2017, 8(25): 39994-40005.

DOI：10.18632/oncotarget.18127

• RUNX1/AML1
• oncoprotein
• translocation
• miRNA
• sponge

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 miR29b-1 and the oncogenic AML1-ETO that controls the leukemic phenotype in t(8;21)-carrying acute myeloid leukemia.

• 出版日期2017-6-20