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

Abstract

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.

Roles and clinical implications of microRNAs in acute lymphoblastic leukemia

“…Also miR‐21 is involved in the regulation of PI3K/Akt/mTOR pathway and the expression of this miRNA is correlated to drug resistance by downregulation of PTEN (Bertacchini et al, ) (Figure ). The three members of the miR‐29 family, ‐a, ‐b, and ‐c, function as tumor suppressor in different neoplasia, including leukemia (Zaidi et al, ; Zhang et al, ). The downregulation of miR‐99‐a and miR‐110 is observed in ALL patients and their expression inhibits cell proliferation in ALL cell lines.…”

RUNX oncoproteins and miRNA networks

“…Moreover, they are expressed from hybrid mRNAs in which the 3′UTR is attached to a new 5′ moiety, creating a novel structure that is likely to perturb the miRNA regulatory network. An interesting example of this phenomenon and its importance for leukemia development is provided by the recent paper from Zaidi in Oncotarget [ 5 ] where the authors show that the tumor suppressive miR-29b-1 forms a negative feedback loop with the RUNX1-ETO fusion protein. This miRNA was first described as a target for positive regulation by RUNX3 in gastric cancer cells [ 6 ] and appears to be down-regulated in t(8;21) cell lines where the promoter is bound by RUNX1-ETO and co-repressors.…”

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“…Moreover, they are expressed from hybrid mRNAs in which the 3'UTR is attached to a new 5' moiety, creating a novel structure that is likely to perturb the miRNA regulatory network. An interesting example of this phenomenon and its importance for leukemia development is provided by the recent paper from Zaidi in Oncotarget [5] where the authors show that the tumor suppressive miR-29b-1 forms a negative feedback loop with the RUNX1-ETO fusion protein. This miRNA was first described as a target for positive regulation by RUNX3 in gastric cancer cells [6] and appears to be down-regulated in t(8;21) cell lines where the promoter is bound by RUNX1-ETO and corepressors.…”

“…This miRNA was first described as a target for positive regulation by RUNX3 in gastric cancer cells [6] and appears to be down-regulated in t(8;21) cell lines where the promoter is bound by RUNX1-ETO and corepressors. Significantly, ectopic expression of miR-29b-1 inhibits cell growth and promotes both apoptosis and terminal differentiation [5].…”

“…Moreover, the t(8;21) translocation often arises in utero long before the appearance of AML and requires secondary mutations to reveal its full oncogenic potential in model systems [3]. If new broadly effective therapies are to be generated it will be important to distinguish the direct effects of RUNX1-ETO such as those described [5] from the stochastic events that drive leukemic cell expansion and progression.…”