Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

Mohr, Sebastian; Doebele, Carmen; Comoglio, Federico; Berg, Tobias; Beck, Julia; Bohnenberger, Hanibal; Alexe, Gabriela; Corso, Jasmin; Ströbel, Philipp; Wachter, Astrid; Beißbarth, Tim; Schnütgen, Frank; Cremer, Anjali; Haetscher, Nadine; Göllner, Stefanie; Rouhi, A. Maureen; Palmqvist, Lars; Rieger, Michael A.; Schroeder, Timm; Bönig, Halvard; Müller‐Tidow, Carsten; Kuchenbauer, Florian; Schütz, Ekkehard; Green, Anthony; Urlaub, Henning; Stegmaier, Kimberly; Humphries, R. Keith; Serve, Hubert; Oellerich, Thomas

doi:10.1016/j.ccell.2017.03.001

Cited by 96 publications

(96 citation statements)

References 83 publications

(111 reference statements)

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“…We further verified that ZNF205‐AS1 increased EGR4 mRNA stability, and therefore up‐regulated EGR4 expression. microRNAs (miRNAs) are well‐known to bind the 3’UTR of target mRNAs and induce the degradation and/or translation inhibition of target mRNAs . The interaction between ZNF205‐AS1 transcript and EGR4 mRNA 3’UTR may protect EGR4 mRNA from miRNAs‐induced degradation, which need further investigation.…”

Section: Discussionmentioning

confidence: 99%

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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Accumulating evidences revealed that long noncoding RNAs (lncRNAs) are frequently implicated in non‐small cell lung cancer (NSCLC). Herein, we reported the identification of a novel NSCLC‐associated functional lncRNA ZNF205 antisense RNA 1 (ZNF205‐AS1). ZNF205‐AS1 was increased in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. Bioinformatics prediction, combined with experimental verification revealed that early growth response 4 (EGR4) directly bound to ZNF205‐AS1 promoter, increased the promoter activity of ZNF205‐AS1, and activated ZNF205‐AS1 transcription. Intriguingly, ZNF205‐AS1 transcript directly interacted with EGR4 mRNA, increased EGR4 mRNA stability, and up‐regulated EGR4 expression via RNA‐RNA interaction. Thus, ZNF205‐AS1 and EGR4 formed a positive feedback loop. Through regulating EGR4, ZNF205‐AS1 activated its own promoter activity. EGR4 was also increased in NSCLC and the expression of ZNF205‐AS1 was significantly positively correlated with EGR4 in NSCLC tissues. Gain‐of‐function and loss‐of‐function assays demonstrated that both ZNF205‐AS1 and EGR4 promoted NSCLC cell growth in vitro and NSCLC tumour growth in vivo. Concurrently depleting ZNF205‐AS1 and EGR4 more significantly repressed NSCLC tumour growth in vivo. Collectively, our study demonstrated that the positive feedback loop between ZNF205‐AS1 and EGR4 promotes NSCLC growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC.

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Section: Discussionmentioning

confidence: 99%

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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“…Syk, a critical signaling mediator downstream of B cell antigen receptor, is another potential target through which miR-146a may impact B cell proliferation. Abrogation of miR-146a-mediated repression of SYK was recently implicated as a major driving factor in Hoxa9/Meis1-induced mouse model of myeloid leukemogenesis (38). Although this exact target interaction may not be applicable to human leukemias because of the lack of any miR-146a binding sites in the human Syk 3′UTR, it is illustrative of the potential role of miR-146a dysfunction in driving a variety of human cancers.…”

Section: Discussionmentioning

confidence: 99%

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Magilnick

Reyes

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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microRNA-146a (miR-146a) has been previously implicated as an essential molecular brake, preventing immune overreaction and malignant transformation by attenuating NF-κB signaling, putatively via repression of the Traf6 and Irak1 genes. The exact contribution of miR-146a–mediated silencing of these genes to the control of immune activation is currently unknown. Therefore, we defined the role of the miR-146a–Traf6 signaling axis in the regulation of immune homeostasis using a genetic epistasis analysis in miR-146a−/− mice. We have uncovered a surprising separation of functions at the level of miR-146a targets. Lowering the Traf6 gene dose and consequent attenuation of NF-κB activation rescued several significant miR-146a−/− phenotypes, such as splenomegaly, aberrant myeloproliferation, and excessive inflammatory responses. In contrast, decreasing Traf6 expression had no effect on the development of the progressive bone marrow failure phenotype, as well as lymphomagenesis in miR-146a−/− mice, indicating that miR-146a controls these biological processes through different molecular mechanisms.

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“…15 In AML, HoxA9 could suppress miR-146a and extend the survival ratio in leukaemia model. 22 To further strengthen the concept that HoxA9 regulates the malignancy of leukaemia through regulating microRNA expression level, this study searched for the potentially involved microRNAs and found that microRNA 663 and 494 are regulated by HoxA9 ( Figure 6). More importantly, this regulation is able to control leukaemia cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo

Chen

Yu²,

et al. 2017

Cell Biochemistry & Function

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Progress in the understanding of the molecular mechanism for acute myeloid leukaemia is of great significance to generate new potential targets for treatment. Recent studies showed that HOXA9, a homeodomain-containing transcription factor, is commonly deregulated in acute leukaemia. In this study, we elucidated the direct correlation between HoxA9 expression and progression of leukaemia using 2 different types of leukaemia cells HL-60 and MOLT-3. The HoxA9 expression level was decreased in leukaemia cells with the treatment of all-trans retinoic acid or arsenic trioxide (As O ). Downregulation of HoxA9 could impair the proliferation and promote the leukaemia cell death. HoxA9 silencing also potentiated the differentiation of leukaemia cells, and in vivo studies demonstrated that HoxA9 downregulation could interfere the tumour growth. Interestingly, HoxA9 silencing also led to the alteration in miRNA expression, mediating the promoting effect on the leukaemia cell differentiation. Therefore, this work provided a promising and potentially efficient target to leukaemia treatment, indicating that HoxA9 is likely to be an ideal candidate in the gene therapy against acute myeloid leukaemia. In this study, we elucidated the critical role of HoxA9 in the proliferation and differentiation of leukaemia cells both in vitro and in vivo. The effect of HoxA9 modulation was correlated with the clinical effect of all-trans retinoic acid and As O . Furthermore, HoxA9 also regulated the miRNA expression, controlling the leukaemia cell differentiation. Therefore, this work provided new insights into molecular mechanism underlying the leukaemia treatment, potentially putting forward a brand new target to the gene therapy against leukaemia.

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Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

Cited by 96 publications

References 83 publications

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo

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