Abstract
BackgroundAcute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML.MethodsThe expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays.ResultsHOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression.ConclusionsTaken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype.
Highlights
Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms
HOTAIRM1 is highly expressed in NPM1‐mutated AML cells To identify the long noncoding RNA (lncRNA) that potentially participate in the progression of NPM1-mutated AML, we analyzed gene expression profiles using public databases (GSE15434 and the cancer genome atlas (TCGA) datasets)
Consistent with these findings, the expression level of HOTAIRM1 was measured by Quantitative real-time PCR (qRT-PCR) in 34 primary AML blasts, and HOTAIRM1 was found to be highly expressed in NPM1-mutated AML cases (n = 14) compared with NPM1- unmutated AML cases (n = 20) (Fig. 1e)
Summary
Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. The biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. We aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML. Jing et al J Exp Clin Cancer Res (2021) 40:312 neoplasms, AML with nucleophosmin (NPM1) mutations was defined as a distinct subtype [2]. NPM1 mutation results in cytoplasmic mislocalization of the mutant protein (NPM1c +), which is critical for its role in leukemogenesis [3]. Novel therapeutic targets should be investigated to improve the diagnosis and treatment of patients with NPM1-mutated AML
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