Flt3 receptor inhibition reduces constitutive NFκB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Grosjean-Raillard, Jennifer; Adès, Lionel; Boehrer, Simone; Tailler, Maximilien; Fabre, Claire; Braun, Thorsten; Botton, Stéphane de; Israël, Alain; Fenaux, Pierre; Kroemer, Guido

doi:10.1007/s10495-008-0243-4

Cited by 37 publications

(36 citation statements)

References 48 publications

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“…Based on the results of MetaCore analysis, we propose that TGFBR2 and FLT3 regulate the growth of HSC-3 cells through activating SHC1 and IKBKB via phosphorylation followed by activation of their downstream signaling pathways, resulting in NF-κB translocation from cytoplasm to nucleus then transcribing genes that promote growth of HSC-3 cells. According to our results and several other reports (26)(27)(28), a putative molecular pathway is proposed in Fig. 2B.…”

Section: Bioinformatics Analysis Reveals Potential Biomarkers and Molsupporting

confidence: 85%

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells

et al. 2011

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Abstract. Oral carcinoma is a serious public health problem and the leading cause of head and neck cancer mortality worldwide. Moreover, oral cancer patients often present symptoms at a late stage and show a high recurrence rate after treatment. Therefore, there is an urgent need to identify novel biomarkers for early diagnosis or clinical oral cancer therapy. In this study, we employed a subset of lentiviral short hairpin RNAs targeted against various kinases and phosphatases, designed by The RNAi Consortium, to screen systemically and in a high-throughput manner for potential growth regulators of oral cancer cells. The screen revealed a total of 50 candidate genes, for which more than 90% of growth inhibition in human oral squamous cancer HSC-3 cells was obtained. Furthermore, bioinformatic analysis of these candidate genes identified transforming growth factor-β receptor type II-and fms-related tyrosine kinase 3-related molecular pathways that are involved in NF-κB-mediated growth of HSC-3 cells. These candidate genes may be potential biomarkers for early diagnosis of oral cancer. In addition, these candidate genes represent potential targets for anticancer drug design helping to develop a personalized treatment to combat oral cancer.

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Section: Bioinformatics Analysis Reveals Potential Biomarkers and Molsupporting

confidence: 85%

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells

et al. 2011

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“…Indeed, the other two cell lines (MOLM-13 and MV4-11) exhibited the constitutive phosphorylation of the oncogenic receptor tyrosine kinase Flt3 and activated NF-kB through activated Flt3, meaning that they readily succumbed upon pharmacological inhibition or depletion of Flt3 (Grosjean-Raillard et al, 2008). In contrast, P39 cells whose NF-kB activation depends on ATM do not express Flt3 and are insensitive to Flt3 inhibitors (Grosjean-Raillard et al, 2008). These observations point to the interesting possibility that different populations of malignant cells (which are represented by different cell lines) use distinct mechanisms for activating NF-kB.…”

Section: Discussionmentioning

confidence: 99%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

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The anti-apoptotic transcription factor nuclear factor-jB (NF-jB) is constitutively activated in CD34 þ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-jB by suppressing the canonical NF-jB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-jB (IjB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-jB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of IjBa and caused the relocalization of NF-jB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-jB subunit, suggesting that an ATM inhibition/ depletion truly induced apoptosis through inhibition of the NF-jB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with highrisk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-jB in high-risk MDS and AML.

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“…Similarly, sustained expression of a human MYC transgene culminated in the formation of AML in mice (33). NFKB1 is a transcription factor that is constitutively activated in primitive human AML cells, while inhibition of NFKB1 displayed a rapid induction of apoptosis in AML cells (32,55). After analyzing the topology of subnetwork, we found that TCF3 was a potential key regulator in our network due to its direct linking to all the four hubs in the subnetworks (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…Moreover, there were three pairs of miRNA→gene regulatory relationships (miR-126-5p and miR-126-3p represses pLK2 and miR-17-5p represses RuNx1) that have been experimentally confirmed in AML (30,31). Two TFs (NFKB1 and Myc) in this network have been reportedly associated with the development of AML (32,33). NFKB1 and Myc transcriptionally suppressed miR-29b-3p expression by binding to its promoter, and MYC was confirmed as a transcriptional repressor of miR-15a-5p, which were in accord with the same TF→miRNA regulatory relationships in our network (34,35).…”

Section: Mirna and Tf Regulatory Network In Amlmentioning

confidence: 78%

“…These findings are a preliminary reflection on the robustness of our network. Among these hub nodes, two hub miRNAs (miR-15a-5p and miR-125b-5p) and two hub TFs (Myc and NFKB1) have been previously implicated in AML (12,32,33,47). To further investigate the regulation of the four hub nodes, we extracted their subnetworks by including all their directly linked nodes in the miRNA-TF regulatory network (Fig.…”

Section: Network Hubs and Subnetwork For Hubs In The Mirna-tf Regulamentioning

confidence: 99%

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Molecular dysfunctions in acute myeloid leukemia revealed by integrated analysis of microRNA and transcription factor

Lin

Sun

et al. 2016

International Journal of Oncology

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Abstract. Acute myeloid leukemia (AML) is a heterogenic hematological malignancy with pathogenesis that has yet to be elucidated. MicroRNAs (miRNAs) and transcription factors (TFs) are two major regulators of gene expression, which may play important roles in the etiology of AML. However, the global regulation of gene expression in AML, involving miRNAs and TFs, still remains elusive. To characterize the global role of miRNAs and TFs in AML pathogenesis, large scale expression profiling of miRNA and TF was performed using miRNA sequencing and TF array technology, respectively, and validated by qPCR. In the present study, 308 miRNAs and 84 TFs were identified to be differentially expressed (fold-change ≥2.0) in AML samples relative to their controls. After integrating the expression profiling data into bioinformatic analysis, we identified 1,462 miRNA-gene pairs, 982 TF-gene pairs and 296 TF-miRNA pairs. By merging these regulatory relations together, we constructed a comprehensive AML-specific miRNA-TF regulatory network. In this network, we identified 22 hub miRNAs and 11 hub TFs. KEGG pathway analysis showed that the network nodes were significantly enriched in 33 different pathways, of which the AML pathway was the most significant. After analyzing the topology of the subnetwork, we propose that TCF3 was a potential key regulator in this regulatory network. In conclusion, this is the first study perform on global expression profiling of miRNAs and TFs relating to AML. These results may enhance our understanding of the molecular mechanisms underlying AML and provide potential targets for future therapeutics.

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Flt3 receptor inhibition reduces constitutive NFκB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Cited by 37 publications

References 48 publications

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Molecular dysfunctions in acute myeloid leukemia revealed by integrated analysis of microRNA and transcription factor

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