Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth

Dave, Kashyap; Sur, Inderpreet; Yan, Jian; Zhang, Jilin; Kaasinen, Eevi; Zhong, Fan; Blaas, Leander; Li, Xiaoze; Kharazi, Shabnam; Gustafsson, Charlotte; Paepe, Annick De; Månsson, Robert; Taipale, Jussi

doi:10.7554/elife.23382

Cited by 56 publications

(64 citation statements)

References 68 publications

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“…The function of MYC, located on chromosome 8q24, is critical for the development of various tumors 21,22 , and the expression of MYC is activated by a gene amplification and the disrupted regulation of tissue-specific enhancers of MYC (e.g. colon cancer, T-ALL) 23–25 . Translocation-induced enhancer hijacking has been shown to activate the expression of oncogenes including MYC (e.g.…”

Section: Introductionmentioning

confidence: 99%

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm

et al. 2019

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53 , providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.

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Section: Introductionmentioning

confidence: 99%

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm

et al. 2019

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“…Mice deficient in multiple Myc enhancers, including Myc-196, Myc-335, and Myc-540, within 538kb upstream of Myc, exhibit >50% reductions of Myc expression in colon and prostate. Importantly, these mice are more protected from APC mutation-induced intestinal cancer compared to mice deficient in only Myc-335 [75]. Both CCAT1 and CCAT2 interact with Myc via the formation of DNA loops, which strongly enhances Myc expression in CRC [17,70,76].…”

Section: Upregulation Of Myc As a Mechanism Underlying The Gene Desermentioning

confidence: 99%

The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert

Lin

Kapoor

et al. 2020

Genes

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FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B and Myc genes border a 1.2 Mb gene desert at 8q24.21. Co-amplification of both occurs in 20 cancer types. Mice deficient of a 430 Kb fragment within the 1.2 Mb gene desert have downregulated FAM84B and Myc expressions concurrent with reduced breast cancer growth. Intriguingly, Myc works in partnership with other oncogenes, including Ras. FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain. This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A 1/2 and O-acyltransferase activities of HRASLS1-5. These enzymatic activities underlie their suppression of Ras. FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5. Deletion of this motif abolishes FAM84B oncogenic activities. These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions. Here, we will discuss recent research on FAM84B-derived oncogenic potential.Genes 2020, 11, 312 2 of 15 non-coding RNA (lnRNA), and on its upstream or centromeric side sits a 1.2 Mb gene desert with the centromeric side bordered by the FAM84B or LRATD2 gene ( Figure 1). The unique feature of this gene desert is the existence of multiple (lnRNAs) (PCAT1, PCAT2, POU5F1B, CCAT1, CCAT2, CASC8, CASC11, CASC19, and CASC21) with FAM84B and Myc being the only protein coding genes (Figure 1) [12][13][14]. In view of Myc being the most-well-studied oncogene and the 8q24 gene desert as a region that is frequently amplified in cancer, FAM84B stands as a promising target for oncogenic activities; nonetheless, its impact on tumorigenesis remained unknown until recently. As the oncogenic potential of the non-coding RNAs of PVT1 and those within the gene desert (Figure 1) has been recently reviewed [13][14][15][16][17], we will focus on the emerging role of FAM84B in tumorigenesis in this review. We will briefly discuss the 8q24 gene desert with respect to oncogenesis to set the stage for the following systemic examination of the evidence pertinent to FAM84B-derived tumorigenesis. The main materials used in this review were chosen based on the PRISMA (preferred reporting items for systematic reviews and meta-analyses) Guidelines [18,19]. A literature search of the PubMed database for (1) "8q24 gene desert", revealed 28 papers with 6 irrelevant to tumorigenesis (Figure 2A) and (2) "FAM84B", identified 21 articles, including non-English papers (n = 1) and articles not directly related to FAM84B and cancer (n = 2) ( Figure 2B). After excluding these items, 22 articles on 8q24 gene desert and 18 papers related to the FAM84B topic h...

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“…Deleting the upstream super enhancer region of Myc in mice specifically affected its expression in tissues like the colon and prostate and led to a partial loss of the mammary tumorigenic phenotype in these mice. 15 While these and other studies validate the increased interest in SEs, this might inadvertently lead to the disregard of important "typical" enhancers that can significantly mediate the effects of BRD4 and may efficiently be exploited in its perturbation.…”

Section: Introductionmentioning

confidence: 87%

Super enhancers – new analyses and perspectives on the low hanging fruit

Hamdan

Johnsen

2017

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Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth

Cited by 56 publications

References 68 publications

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm

The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert

Super enhancers – new analyses and perspectives on the low hanging fruit

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