The stem cell–specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia

Al-Kershi, Sina; Bhayadia, Raj; Ng, Michelle; Verboon, Lonneke; Emmrich, Stephan; Gack, Lucie; Schwarzer, Adrian; Strowig, Till; Heckl, Dirk; Klusmann, Jan‐Henning

doi:10.1182/bloodadvances.2019032029

Cited by 25 publications

(20 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, our findings were supported by those of a previous study indicating that HOTAIRM1 expression was elevated in myeloid leukemia cells [ 18 , 21 ]. Additionally, other HOX cluster lncRNAs, such as HOXA10-AS and HOXB-AS3, have been reported to be significantly overexpressed in NPM1-mutated leukemia cells [ 39 , 41 ]. Deregulated lncRNAs have prognostic applications in AML [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background 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. 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. Methods The 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. Results HOTAIRM1 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. Conclusions Taken 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Indeed, among the AR-interacting lncRNAs experimentally proved in this study, AL031714.1 and AC110285.1 expression correlated with tumor malignancy, and high AL031714.1 levels contributed to a bad prognosis. Moreover, HOXA10-AS was recently demonstrated to promote cell proliferation of lung adenocarcinoma [53] and KMT2A -rearranged leukemia [54] , although its expression was not found to correlate with either tumor grade or survival in prostate cancer. Thus, the interacting lncRNA partners of the prognostic signature constituent transcription factors may represent potential biomarkers and/or therapeutic targets in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional network modulated by the prognostic signature transcription factors and their long noncoding RNA partners in primary prostate cancer

et al. 2021

View full text Add to dashboard Cite

Background Transcriptional regulators are seminal players in the onset and progression of prostate cancer. However, clarification of their underlying regulatory circuits and mechanisms demands considerable effort. Methods Integrated analyses were performed on genomic, transcriptomic, and clinicopathological profiles of primary prostate cancer and transcription factor-binding profiles, which included estimating transcription factor activity, identifying transcription factors of prognostic values, and discovering cis - and trans -regulations by long noncoding RNAs. Interactions between transcription factors and long noncoding RNAs were validated by RNA immunoprecipitation quantitative PCR. RNA interference assays were performed to explore roles of the selected transcription regulators. Findings Sixteen transcription factors, namely, ETS1, ARID4B, KLF12, GMEB1, HBP1, MXI1, MYC, MAX, PGR, BCL11A, AR, KLF4, SRF, HIF1A, EHF, and ATOH1, were jointly identified as a prognostic signature. Candidate long noncoding RNAs interplaying with the prognostic signature constituent transcription factors were further discovered. Their interactions were randomly checked, and many of them were experimentally proved. Transcription regulation by MYC and its long noncoding RNA partner AL590617.2 was further validated on their candidate targets. Moreover, the regulatory network governed by the transcription factors and their interacting long noncoding RNA partners is illustrated and stored in our LNCTRN database ( https://navy.shinyapps.io/lnctrn ). Interpretation The prognostic signature constituent transcription factors and their interacting long noncoding RNAs may represent promising biomarkers and/or therapeutic targets for prostate cancer. Furthermore, the computational framework proposed in the present study can be utilized to explore critical transcriptional regulators in other types of cancer. Funding This work was supported by National Natural Science Foundation of China and Fudan University.

show abstract

“…Several lncRNAs are implicated in GC, such as HOTAIR [ 12 ], NEAT1 [ 13 ], and LINC01410 [ 14 ]. HOXA10 antisense RNA (HOXA10-AS) is a lncRNA and transcribed antisense to HOXA10 [ 15 ]. Intriguingly, HOXA10-AS is upregulated and functions as an oncogene in various cancers including leukemia [ 15 ], glioma [ 16 ], and oral cancer [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…HOXA10 antisense RNA (HOXA10-AS) is a lncRNA and transcribed antisense to HOXA10 [ 15 ]. Intriguingly, HOXA10-AS is upregulated and functions as an oncogene in various cancers including leukemia [ 15 ], glioma [ 16 ], and oral cancer [ 17 ]. Dong and colleagues reported that HOXA10-AS expression was elevated in glioma, and HOXA10-AS promoted glioma cell proliferation and enhanced apoptosis via activating HOXA10 expression [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

+HOXA10-AS Promotes Malignant Phenotypes of Gastric Cancer via Upregulating HOXA10

Cao

Zheng

Yang

et al. 2022

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Objective. To study the role of long noncoding RNA HOXA10-AS in gastric cancer (GC) and its underlying mechanism which is one of the most common and fetal malignancies. Long noncoding RNA HOXA10-AS is highly expressed and acts in an oncogenic role in cancers. However, its roles in GC are still unknown. Methods. The expression of HOXA10-AS and HOXA10 in GC tissues from the TCGA database was analyzed. Western blot and qRT-PCR assays were applied to examine the expression of HOXA10-AS and HOXA10. Cell proliferation was evaluated with CCK-8 and EdU incorporation assays. Cell apoptosis was analyzed by flow cytometry. Migratory and invasive capacities were evaluated with wound healing and transwell assays. Results. HOXA10-AS and HOXA10 were upregulated in GC, and their expressions were positively correlated. Knockdown of HOXA10-AS inhibited HOXA10 expression in GC cells. Furthermore, knockdown of HOXA10-AS restrained GC cell proliferation, migration, and invasion but promoted apoptosis. In addition, overexpression of HOXA10-AS promoted malignant phenotypes of GC cells, but all these effects could be reversed by knockdown of HOXA10. Conclusion. HOXA10-AS promoted GC cell proliferation, migration and invasion and enhanced apoptosis via upregulating HOXA10. Our study implies a novel regulatory mechanism of malignant phenotypes and provides potential therapeutic targets for GC.

show abstract

The stem cell–specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia

Cited by 25 publications

References 47 publications

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Transcriptional network modulated by the prognostic signature transcription factors and their long noncoding RNA partners in primary prostate cancer

+HOXA10-AS Promotes Malignant Phenotypes of Gastric Cancer via Upregulating HOXA10

Contact Info

Product

Resources

About