High Expression of TET1 Predicts Poor Survival in Cytogenetically Normal Acute Myeloid Leukemia From Two Cohorts

Wang, Jinghan; Li, Fenglin; Ma, Zeyu; Yu, Mengxia; Guo, Qi; Huang, Jiansong; Yu, Wenjuan; Wang, Yungui; Jin, Jie

doi:10.1016/j.ebiom.2018.01.031

Cited by 29 publications

(31 citation statements)

References 41 publications

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“…We applied a meta-analysis of mRNA expression to our 22 CN-AML patients with previously published gene expression dataset [15], 165 patients from the GSE1159 dataset and 197 patients from the TCGA dataset profiles to explore the biological insights of low ACLY expression. We found 390 genes were down-regulated and 111 genes were upregulated in the low ACLY group using the false discovery rate (FDR < 0.05; Additional file 1: Table S5, Figure S3).…”

Section: Resultsmentioning

confidence: 99%

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Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia

Wang

Yan

et al. 2019

J Transl Med

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Background Aberrant metabolism is a hallmark of cancer cells. Recently, ATP citrate-lyase ( ACLY ) expression was demonstrated as an independent predictor of clinical outcome in solid tumors. However, no systematic study was conducted to explore the prognostic impact of ACLY on acute myeloid leukemia (AML). Methods To assess the prognostic value of ACLY transcript, we conducted a study with a discovery and validation design. We measured ACLY transcript by real-time quantitative PCR in 274 AML patients, and validated the prognostic value in the two independent cohorts using published data. Meta-analysis of gene-expression profile and inhibition ACLY expression in leukemia cell lines were conducted to help us understand the biological insight of low ACLY expression. Results Low ACLY expression is less common amongst AMLs with DNMT3A mutations, but coexisted in double allele CEBPA mutations. Moreover, low ACLY expression is associated with favorable overall survival in AML patients and is involved in multiple pathways. These results are also validated in two independent cohorts of AML patients. Moreover, ACLY silencing induces proliferation arrest in THP-1 and MOLM-13 leukemia cell lines. Conclusion We found low ACLY expression is associated with favorable overall survival in AML patients. Electronic supplementary material The online version of this article (10.1186/s12967-019-1884-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…We excluded patients with acute promyelocytic leukemia in this study. WHO classification, cytogenetic risk classification and treatment protocols were reported previously [2, 4, 15]. Cellular materials were stored at the department of hematology in our hospital.…”

Section: Methodsmentioning

confidence: 99%

Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia

Wang

Yan

et al. 2019

J Transl Med

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“…Quantitative real-time polymerized chain reaction (qRT-PCR) was performed as previously described. 40 Total RNA was extracted from the cells using TRIzol reagent. Single-stranded cDNA was synthesized from 0.5 µg of total RNA using Prime-Script RT Master Mix according to the manufacturer's protocol (TaKaRa Bio, Dalian, China).…”

Section: Quantitative Real-time Polymerized Chain Reactionmentioning

confidence: 99%

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

Huang

et al. 2020

Thromb Haemost

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Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, has a favorable safety profile in patients with B cell-related malignancies. A primary adverse effect of ibrutinib is thrombocytopenia in the early stages of treatment, but platelet counts increase or recover as treatment continues. Currently, the effects of ibrutinib on megakaryopoiesis remain unclear. In this study, we investigated the mechanism by which ibrutinib induces thrombocytopenia using cord blood CD34+ hematopoietic stem cells (HSCs), a human megakaryoblastic cell line (SET-2), and C57BL/6 mice. We show that treatment with ibrutinib can suppress CD34+ HSC differentiation into megakaryocytes (MKs) and decrease the number of colony-forming unit-MKs (CFU-MKs). The ibrutinib-dependent inhibition of early megakaryopoiesis seems to mainly involve impaired proliferation of progenitor cells without induction of apoptosis. The effects of ibrutinib on late-stage megakaryopoiesis, in contrast to early-stage megakaryopoiesis, include enhanced MK differentiation, ploidy, and proplatelet formation in CD34+ HSC-derived MKs and SET-2 cells. We also demonstrated that MK adhesion and spreading, but not migration, were inhibited by ibrutinib. Furthermore, we revealed that integrin αIIbβ3 outside-in signaling in MKs was inhibited by ibrutinib. Consistent with previous clinical observations, in C57BL/6 mice treated with ibrutinib, platelet counts decreased by days 2 to 7 and recovered to normal levels by day 15. Together, these results reveal the pathogenesis of ibrutinib-induced transient thrombocytopenia. In conclusion, ibrutinib suppresses early megakaryopoiesis, as evidenced by inhibition of MK progenitor cell proliferation and CFU-MK formation. Ibrutinib enhances MK differentiation, ploidy, and proplatelet formation, while it impairs integrin αIIbβ3 outside-in signaling.

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“…Members of the TET protein family play a role in the DNA methylation process and gene activation. High expression of TET1 indicates a poor prognosis in cytogenetically normal acute myeloid leukemia (Wang et al, 2018) and promotes cisplatin-resistance in ovarian cancer (Han et al, 2017). As for the competing pairs, miR-29b/c was shown to suppress the downstream gene DNMT3A, and in turn, miR-29b/ c was suppressed by DNMT3A in a DNA methylationdependent manner in gastric cancer (He et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Integrative Clustering Reveals a Novel Subtype of Soft Tissue Sarcoma With Poor Prognosis

et al. 2020

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Background: Soft tissue sarcomas (STSs) are heterogeneous at the clinical and molecular level and need to be further sub-clustered for treatment and prognosis. Materials And Methods: STSs were sub-clustered based on RNAseq and miRNAseq data extracted from The Cancer Genome Atlas (TCGA) through the combined process of similarity network fusion (SNF) and consensus clustering (CC). The expression and clinical characteristics of each sub-cluster were analyzed. The genes differentially expressed (lncRNAs, miRNAs, and mRNAs) between the poor prognosis and good prognosis clusters were used to construct a competing endogenous RNA (ceRNA) network. Functional enrichment analysis was conducted and a hub network was extracted from the constructed ceRNA network. Results: A total of 247 STSs were classified into three optimal sub-clusters, and patients in cluster 2 (C2) had a significantly lower rate of survival. A ceRNA network with 91 nodes and 167 edges was constructed according to the hypothesis of ceRNA. Functional enrichment analysis revealed that the network was mainly associated with organism development functions. Moreover, LncRNA (KCNQ1OT1)-miRNA (has-miR-29c-3p)-mRNA (JARID2, CDK8, DNMT3A, TET1)-competing endogenous gene pairs were identified as hub networks of the ceRNA network, in which each component showed survival significance. Conclusion: Integrative clustering analysis revealed that the STSs could be clustered into three sub-clusters. The ceRNA network, especially the subnetwork LncRNA (KCNQ1OT1)-miRNA (has-miR-29c-3p)-mRNA (JARID2, CDK8, DNMT3A, TET1) was a promising therapeutic target for the STS sub-cluster associated with a poor prognosis.

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High Expression of TET1 Predicts Poor Survival in Cytogenetically Normal Acute Myeloid Leukemia From Two Cohorts

Cited by 29 publications

References 41 publications

Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia

Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

Integrative Clustering Reveals a Novel Subtype of Soft Tissue Sarcoma With Poor Prognosis

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