A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Abstract

MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 downregulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex. In this study, we demonstrate that miR-9-1 expression increases significantly after the treatment of RUNX1-RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1 by binding to RUNX1-binding sites in the promoter region of miR-9-1 and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR-9-1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1-RUNX1T1 are all regulated by miR-9-1, the silencing of miR-9-1 enhances the oncogenic activity of these genes. Besides, overexpression of miR-9-1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1, contributing to leukemogenesis in RUNX1-RUNX1T1 (+) AML cell lines.

Role of HDACs in normal and malignant hematopoiesis

“…Furthermore, HDACs are critical for the optimal oncogenic activity of leukemia fusion proteins. For example, AML1-ETO, PML-RARα and RARα-PLZF cause transcriptional repression of genes responsible for hematopoietic differentiation via recruitment of HDAC1/3, thus contributing substantially to leukemogenesis [99][100][101][102][103][104][105][106][107]. Given that the expression and activity of HDACs are closely related to the etiology of hematological malignancies, HDACs are hot targets for clinical drug development.…”

Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia

“…In another study, miR-9-1 was observed to be downregulated in t(8;21) AML. Besides, overexpressed miR-9-1 induced differentiation and inhibited proliferation in t(8;21) AML cell lines [13]. MiR-10a/b was significantly increased in AML patients with t(8;21), t(9;11), NPM1 mutation, and particularly M1, M2, and M3 subtype.…”

“…Silencing of miR-9-1 promoted expression of target genes(RUNX1, RUNX1T1, and RUNX1-RUNX1T1), which inhibited differentiation and promoted the proliferation of t(8; 21) AML cell lines [13] ↑3YPERLINK \lline ERG ERG is a direct target of miR-9 which contributed to miR-9/9*-induced differentiation of progenitor cells towards neutrophils [33] ↑3YPERLINK \l "_ENREF_33" \o "Nowek K, 2016 #298" hor><Yeaparients with normal karyotype Hes1 miR-9 negatively regulated Hes1 expression and knockdown of miR-9 suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro, decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model [34] ↓in AE-positive cell lines SIRT1 Knockdown of SIRT1 expression inhibits cell proliferation in AE-positive AML cell lines [87] ↓in EVI1-induced AML FOXO1 FOXO3…”

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

“…Additionally, new information indicates a feedback minicircuitry through which the expression of miR-9-1 was decreased by AML1-ETO repression activity, leading to increasing level of RUNX1, RUNX1T1, and RUNX1-RUNX1T1, which are all targeted by miR-9-1 ( Figure 5) [26]. As thanatos-associated protein 10 (THAP10) is a nuclear protein that inhibits myeloid proliferation and promotes differentiation both in vitro and in vivo, AML1-ETO inhibits expression of the tumor suppressor THAP10 directly via epigenetic suppression of the THAP10 promoter and indirectly through transcriptional activation of miR-383 in t(8;21) AML, unveiling a novel epigenetic mini-circuitry of AML1-ETO/THAP10/miR-383 [28].…”

“…This model might be oversimplified; however, there is convincing evidence supporting the hypothesis that leukemias are induced by cooperation between alterations in protein-coding genes and microRNAs (miRNAs), an entire novel epigenetic targets linked to leukemia development [22]. The consequences of altered expression and epigenetic status of miRNAs in CBF leukemias have been reported by us and other groups, unveiling that microRNAs are extensively integrated into the molecular networks that control leukemic development and progression [23][24][25][26][27][28]. Therefore, in this review, we summarize a synopsis of recent studies on comprehensive molecular profiles in CBF leukemias, providing a rationale for translation of the accumulating molecular evidence into clinical trials for better therapies to CBF leukemia patients.…”