TET2 and DNMT3A mutations and exceptional response to 4′-thio-2′-deoxycytidine in human solid tumor models

Yang, Sherry X.; Hollingshead, Melinda G.; Rubinstein, Larry; Nguyen, Dat; Larenjeira, Angelo B. A.; Kinders, Robert J.; Difilippantonio, Michael J.; Doroshow, James H.

doi:10.1186/s13045-021-01091-5

Cited by 7 publications

(6 citation statements)

References 29 publications

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“…Clonogenic cell survival assay. The test has been described in detail previously 41 . Briefly, 150,000 cells were treated with increasing concentrations of DNMTi for 48 h. After washing, 2,000 cells/well in triplicates were plated in 6 wells plates for 8-14 days.…”

Section: Dnmt1 Gene Disruption In Mcf7 Cells By Crispr Methodmentioning

confidence: 99%

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DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors

Laranjeira

Hollingshead

Nguyen

et al. 2023

Sci Rep

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Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1−/−) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4′-thio-2′-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G2/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1+/+ versus DNMT1−/− status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice bearing HCT116 DNMT1+/+ xenograft and bladder PDX tumors. DNMT1 gene deletion occurred in ~ 9% human colon cancers and other cancer types at varying degrees. Decitabine and azacitidine demethylated CDKN2A/CDKN2B genes in DNMT1+/+ and DNMT1−/− conditions and increased histone-H3 acetylation with re-expression of p16INK4A/p15INK4B in DNMT1−/− state. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.

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Section: Dnmt1 Gene Disruption In Mcf7 Cells By Crispr Methodmentioning

confidence: 99%

“…Western blotting. Western blotting method has been described previously 41 . Briefly, 50 µM of protein were electrophoresed on 7.5% or 4-20% SDS-polyacrylamide gels (Bio-Rad, Hercules, CA, USA).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors

Laranjeira

Hollingshead

Nguyen

et al. 2023

Sci Rep

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“…Besides, Yang demonstrated that concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment in vitro and in vivo. 39 For copy number variations, the RMCS2 contained higher CNV amplification and deletion frequencies than the RMCS1. Some RNA modification-related genes were contained in these mutated regions, such as HNRNPAB, CDKN2B, and FGFR4.…”

Section: Discussionmentioning

confidence: 95%

“…TET2 could suppress VHL deficiency‐driven clear cell RCC by inhibiting HIF signaling. Besides, Yang demonstrated that concurrent mutations in TET2 and DNMT3A were sensitive to T‐dCyd treatment in vitro and in vivo 39 . For copy number variations, the RMCS2 contained higher CNV amplification and deletion frequencies than the RMCS1.…”

Section: Discussionmentioning

confidence: 98%

RNA modification pattern‐based subtypes reveal heterogenous clinical outcomes and tumor immunity of clear cell renal cell carcinoma

Jiang

Xiao

et al. 2023

MedComm – Future Medicine

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RNA methylation plays a key role across biological processes, which could be utilized as new weapons for cancer management. However, the implication of RNA methylation regulators in cancers, especially in clear cell renal cell cancer (ccRCC), remains largely unknown. We investigated the multiomics profile of RNA methylation regulators at the pan-cancer level. We found most RNA methylation regulators were dysregulated in cancers, which might be explained by genomic mutation and copy number variation. A novel subtype of ccRCC, RNA modification cancer subtype 2 (RMCS2), was identified and verified among different ccRCC cohorts. RMCS2 led to a shortened overall survival and had an activated state of PI3K-AKT-mTOR, KRAS, and retinoic acid metabolism signals, which resulted in an immune exhausted phenotype. In summary, our findings demonstrated that the aberrance of RNA methylation regulators was a common biological phenomenon pan-cancer. Dysregulated RNA methylation patterns could reshape tumor immunity thus impacting patients' prognosis and therapeutic response, and could function as a promising tool for ccRCC patients.

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“…Second, the variations in other associated genes might effected the phenotypes of DNMT3A. It is evident that there are some genes frequently co-occurrence with DNMT3A variants in haematopoietic malignancy including FLT3, TET2, NPM1, IDH1, IDH2, JAK2 and CEBPA [4,[12][13][14][15][16], while in neurodevelopmental disorders including MeCP2, NSD1 [17][18][19]. Polonis [20] describe a 5-year-old female with a paternally inherited pathogenic variation in EZH2 (c.2050C > T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain signi cance at 2p23.3 (encompassing ve genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 months.…”

Section: Discussionmentioning

confidence: 99%

Growth retardation associated with a novel DNMT3A variation in a Chinese boy: A Case Report

Wang

Yang

Zhang

2023

Preprint

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Background The human gene DNMT3A (DNA methyltransferase 3 alpha) is involved in DNA de novo methylation essential for genome regulation and development. Pathogenic variants in DNMT3A are most commonly associated with variable overgrowth (such as Tatton-Brown-Rahman Syndrome, TBRS), intellectual disability, autism spectrum disorder (ASD) and acute myeloid leukemia (AML). We identified a de novo DNMT3A variant in a Chinese boy with growth retardation. Case presentation A 2.8-year boy was hospitalized with a complaint of growth retardation for 24 months. He was born at 38 weeks of gestation. He showed obviously growth retardation since 3 months of age later, including weight and height. His motor and intellectual developmental milestone were slightly delayed. He began to rise head and turn over at 4 months, sit at 6 months, crawl at 7 months and work at 18 months, respectively. He began to speak a single word at 12 months and could speak few words at 2 years. At admission at 2.8 years of age, his weight was 9.6 kg (< P3th), height was 85.4 cm (< P3th), and head circumference was 45.2 cm (< P3th). He could run but could not jump with two feet, he could follow easy and simple instructions. Physical examination revealed no abnormal signs, especially no abnormal dysmorphic features. A de novo DNMT3A variant, c.911_913del (p.S304del), was identified using next-generation sequencing. His growth retardation was associated with DNMT3A variation. Conclusion We reported here the first case presented with growth retardation who was associated with a de novo DNMT3A variation in a Chinse boy. Our report has expanded on the clinical phenotype of the DNMT3A gene, which can also associated with growth retardation besides overgrowth.

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TET2 and DNMT3A mutations and exceptional response to 4′-thio-2′-deoxycytidine in human solid tumor models

Cited by 7 publications

References 29 publications

DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors

DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors

RNA modification pattern‐based subtypes reveal heterogenous clinical outcomes and tumor immunity of clear cell renal cell carcinoma

Growth retardation associated with a novel DNMT3A variation in a Chinese boy: A Case Report

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