Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia

Bempt, Marlies Vanden; Demeyer, Sofie; Broux, Michaël; Bie, Jolien De; Bornschein, Simon; Mentens, Nele; Vandepoel, Roel; Geerdens, Ellen; Radælli, Enrico; Bornhäuser, Beat; Kulozik, Andreas E.; Meijerink, Jules P.P.; Bourquin, Jean‐Pierre; Bock, Charles E. de; Cools, Jan

doi:10.1016/j.ccell.2018.07.007

Cited by 49 publications

(38 citation statements)

References 72 publications

(116 reference statements)

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“…It was reported that miR-133b impacted the development of CRC by regulating NUP214. Nucleopore is essential for many species to enter the nucleus, and NUP214 regulates mitosis and promotes carcinogenesis (39). NUP214 is involved in impeding mitotic progression and is a reported target of miR-133b; it is also highly expressed in HCT116 cells (12).…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA LINC00114 Facilitates Colorectal Cancer Development Through EZH2/DNMT1-Induced miR-133b Suppression

Chen

et al. 2019

Front. Oncol.

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This study aimed to identify the roles of the long non-coding RNA LINC00114 in colorectal cancer (CRC) development. The expression levels of LINC00114 and miR-133b in CRC were determined by reverse transcription (RT)-polymerase chain reaction (PCR) and the functions of LINC00114 in CRC were evaluated in vitro and in vivo. Methylationspecific PCR assay was performed to detect the miR-133b promoter methylation in CRC cells. Bioinformatics analysis, RNA immunoprecipitation, dual luciferase assay, RNA pull-down, co-immunoprecipitation (IP), and chromatin IP (ChIP) assays were used to elucidate whether LINC00114 could recruit EZH2/DNMT1 and bind to the miR-133b promoter region, leading to dysregulated methylation and the depression of miR-133b. The expression levels of DNA methyltransferases (DNMTs), EZH2, and nucleoporin 214(NUP214) were analyzed by western blotting. Data showed that LINC00114 was highly expressed, whereas miR-133b was downregulated in the CRC tissues and cells. In vitro, silencing LINC00114 inhibited cell proliferation and impeded cell cycle at the G1/S phase by upregulating miR-133b. In vivo, LINC00114 knockdown reduced tumor growth. Further analysis showed that the methylation in miR-133b promoter region was increased in the CRC and silencing LINC00114 increased miR-133b expression through depressing methylation of its promoter region. ChIP-PCR experiments demonstrated that EZH2 and DNMT1 could bind to the miR-133b promoter region and it was abolished by LINC00114 knockdown. sh-EZH2 reversed the overexpression of DNMTs and CRC cell cycle progression induced by the LINC00114 upregulation. LINC00114 could regulate the NUP214 protein expression by sponging miR-133b. These results demonstrated that LINC00114 suppressed miR-133b expression via EZH2/DNMT1-mediated methylation of its promoter region, indicating that LINC00114 might be a potential novel target for CRC diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA LINC00114 Facilitates Colorectal Cancer Development Through EZH2/DNMT1-Induced miR-133b Suppression

Chen

et al. 2019

Front. Oncol.

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“…Similarly, RUNX1 binds to N-Me, and secondary deletion of RUNX1 in already established T-ALLs abrogated the binding of NOTCH1 and resulted in impaired transcription of MYC [42]. In addition, it has been recently described that NUP214-ABL1/TLX1-positive T-ALL cases are characterized by a STAT5 gene signature in which both STAT5 and TLX1 cooperatively bind the N-Me enhancer to promote MYC expression [43]. Overall, these results highlight the role of N-Me as a major enhancer node driving T-cell proliferation and transformation through the integration of input signals from NOTCH1 and additional transcription factors.…”

Section: Long-range Regulation Of Myc In Hematological Malignanciesmentioning

confidence: 99%

The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer

Lancho

Herranz

2018

Trends in Cancer

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MYC is one of the most important oncogenes in cancer. Indeed, MYC is upregulated in 50–60% of all tumors. MYC overexpression can be achieved through a variety of mechanisms, including gene duplications, chromosomal translocations or somatic mutations leading to increased MYC stability. However, recent studies have identified numerous tissue-specific non-coding enhancers of MYC that play major roles in cancer, highlighting long-range transcriptional regulation of MYC as a critical novel mechanism leading to MYC hyperactivation and as a potential target for new therapeutic strategies in the near future. Here, we summarize the regions and mechanisms involved in the long-range transcriptional regulation of MYC, underscoring the relevance of MYC enhancers both in normal physiological development and in MYC-driven cancer initiation and progression.

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“…As described previously, this super-enhancer is also essential for normal T cell differentiation. A more detailed analysis revealed that STAT5 and TLX1 co-bound and activated the N-Me and in the regulation MYC and BCL2 expression and promoted the development of T-ALL with NUP214-ABL1 fusion [73].…”

Section: Focal Amplification Of Super-enhancersmentioning

confidence: 99%

Super-enhancers: critical roles and therapeutic targets in hematologic malignancies

2019

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Super-enhancers (SEs) in a broad range of human cell types are large clusters of enhancers with aberrant high levels of transcription factor binding, which are central to drive expression of genes in controlling cell identity and stimulating oncogenic transcription. Cancer cells acquire super-enhancers at oncogene and cancerous phenotype relies on these abnormal transcription propelled by SEs. Furthermore, specific inhibitors targeting SEs assembly and activation have offered potential targets for treating various tumors including hematological malignancies. Here, we first review the identification, functional significance of SEs. Next, we summarize recent findings of SEs and SE-driven gene regulation in normal hematopoiesis and hematologic malignancies. The importance and various modes of SE-mediated MYC oncogene amplification are illustrated. Finally, we highlight the progress of SEs as selective therapeutic targets in basic research and clinical trials. Some open questions regarding functional significance and future directions of targeting SEs in the clinic will be discussed too.

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Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia

Cited by 49 publications

References 72 publications

Long Non-coding RNA LINC00114 Facilitates Colorectal Cancer Development Through EZH2/DNMT1-Induced miR-133b Suppression

Long Non-coding RNA LINC00114 Facilitates Colorectal Cancer Development Through EZH2/DNMT1-Induced miR-133b Suppression

The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer

Super-enhancers: critical roles and therapeutic targets in hematologic malignancies

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