Deregulated Polycomb functions in myeloproliferative neoplasms

Sashida, Goro; Oshima, Motohiko; Iwama, Atsushi

doi:10.1007/s12185-019-02600-6

Cited by 11 publications

(7 citation statements)

References 79 publications

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“…The H3K 2 7me3 then recruits PRC complex 1 to further mediate repression of gene expression. Alterations in BMI1 and EZH 2 and other polycomb components frequently occurs in cancer [59,60] . Little is known concerning alterations in histone modifiers in TGCTs [61,62] .…”

Section: Epigenetics Of Tgctsmentioning

confidence: 99%

Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors

Singh¹,

Fazal²,

Freemantle³

et al. 2019

CDR

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Testicular germ cell tumors (TGCTs) are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting. Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. However, a significant percentage of patients are, or become, refractory to cisplatin and die from progressive disease. Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting. Recently, this promise has been heightened by the realization that distinct (and perhaps pharmacologically replicable) epigenetic states, rather than fixed genetic alterations, may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies. In this review, it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.

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Section: Epigenetics Of Tgctsmentioning

confidence: 99%

Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors

Singh¹,

Fazal²,

Freemantle³

et al. 2019

CDR

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“…Epigenetic modifier genes, such as DNMT3A , TET2 , ASXL1 , and EZH2 , are frequently mutated in MDS and MPN 10 – 12 . A dysregulated function of these epigenetic regulators induces the reprogramming of DNA and/or histone modifications, leading to the induction of MDS or MPN-like diseases in mice 13 – 15 . Of note, recurrent somatic mutations with clonal hematopoiesis have been identified in healthy elderly individuals using comprehensive genome sequencing 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells

et al. 2022

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Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here, we present an integrated analysis of transcriptome and chromatin accessibility of aged HSCs and downstream progenitors. Alterations in chromatin accessibility preferentially take place in HSCs with aging, which gradually resolve with differentiation. Differentially open accessible regions (open DARs) in aged HSCs are enriched for enhancers and show enrichment of binding motifs of the STAT, ATF, and CNC family transcription factors that are activated in response to external stresses. Genes linked to open DARs show significantly higher levels of basal expression and their expression reaches significantly higher peaks after cytokine stimulation in aged HSCs than in young HSCs, suggesting that open DARs contribute to augmented transcriptional responses under stress conditions. However, a short-term stress challenge that mimics infection is not sufficient to induce persistent chromatin accessibility changes in young HSCs. These results indicate that the ongoing and/or history of exposure to external stresses may be epigenetically inscribed in HSCs to augment their responses to external stimuli.

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“…These included mutations in WT1 and loss of heterozygosity at chromosome 11p, which are among the more common changes found in pediatric Wilms tumors. We also found recurrent mutations in genes less commonly associated with pediatric Wilms tumor, such as the ASXL transcriptional regulator one ( ASXL1 ) gene 49,50. The latter is one of the more commonly mutated genes in clonal hematopoiesis, myeloid malignancies, and small cell lung carcinoma and is a known epigenetic regulator which binds to BAP1.…”

Section: Discussionmentioning

confidence: 84%

Adult Wilms Tumor

Argani¹,

Tickoo

Matoso

et al. 2022

American Journal of Surgical Pathology

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The genetics of nephroblastoma (Wilms tumor) occurring in adults is largely unknown, as studies have largely been limited to isolated case reports. We, therefore, studied 14 adult Wilms tumors for genetic alterations, using expanded targeted sequencing on 11 cases. The patients ranged from 17 to 46 years of age (mean and median, 31 y), and there were 8 males and 6 females. Five Wilms tumors harbored BRAF V600E mutations. All of these had better-differentiated areas identical to metanephric adenoma, as has previously been described. In 3 such cases, microdissection studies revealed that the BRAF V600E mutation was present in both the metanephric adenoma and Wilms tumor areas; however, additional genetic alterations (including TERT promoter mutations in 2 cases, ASLX1/ATR mutations in 1 other case) were limited to the Wilms tumor component. These findings suggest that the Wilms tumor developed from the metanephric adenoma. Other adult Wilms tumors harbored genetic alterations previously reported in the more common pediatric Wilms tumors, including WT1 mutations (2 cases), ASLX1 mutations (3 additional cases), NSD2 mutation (1 additional case), and 11p loss (3 cases). In summary, a significant subset of adult Wilms tumors (specifically those of epithelial type with differentiated areas) harbor targetable BRAF V600E mutations and appear to arise from metanephric adenomas as a consequence of additional acquired genetic alterations. Other adult Wilms tumors often harbor genetic alterations found in their more common pediatric counterparts, suggesting at least some similarities in their pathogenesis.

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Deregulated Polycomb functions in myeloproliferative neoplasms

Cited by 11 publications

References 79 publications

Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors

Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors

Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells

Adult Wilms Tumor

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