AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation

Gao, Xuefeng; Yan, Fei; Jiang, Lin; Gao, Li; Lu, Xiao-Lin; Wei, Shengcai; Shen, Na; Pang, Jiuxia; Ning, Qiaoyang; Komeno, Yukiko; Deng, Ailing; Xu, Yihan; Shi, Jianxin; Li, Y. H.; Zhang, D. E.; Nervi, Clara; Liu, Shujun; Yu, Li

doi:10.1038/leu.2015.56

Cited by 77 publications

(96 citation statements)

References 49 publications

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“…The transfection of shRNA, expression or vehicle vectors was performed using Lipfectomine as previously described [36, 44, 45]. Briefly, H69R and H82R cells (2×10 5 ) were seeded into 6-well plates overnight and then transfected with ~2.5 μg shRNA, expression or vehicle vectors using Lipofectamine ™ 2000 reagent (Life Technologies, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells

et al. 2016

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Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC.

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Section: Methodsmentioning

confidence: 99%

Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells

et al. 2016

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“…Given the multiple genome-wide activities associated with Dnmt3a, such as de novo methylation (Okano et al, 1999), maintenance methylation (Jeong, M. et al, 2014), and methylation-independent repression (Datta et al, 2005), it is not surprising that under some circumstances Dnmt3a may promote the development of hematologic malignancies. For example, upregulation of Dnmt3a promotes AML/ETO induced leukemia through de novo hypermethylation (Gao et al, 2015) and methylation-independent repressor function enhances T cell lymphomagenesis (Haney et al, 2015). Such studies highlight the importance of context-dependent activities of Dnmt3a in hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

et al. 2016

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SUMMARY DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that by 16 months of age, 65% of Dnmt3a+/− mice develop a CLL-like disease and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/− and Dnmt3aΔ/Δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene-expression analysis identified 26 hypomethylated and over-expressed genes common to both Dnmt3a+/− and Dnmt3aΔ/Δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

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“…Globally, elevated levels of HIF-1α have been reported in AML [103][104][105][106], APL [100], acute lymphoblastic leukemia (ALL) [107], and chronic myelogenous leukemia (CML) [108,109]. Furthermore, HIF-1α overexpression conditions disease severity and outcome in both AML and myelodysplastic syndrome (MDS) [110][111][112].…”

Section: Migliavacca and Coll Have Recently Demonstrated Oncogenic Fmentioning

confidence: 99%

High Doses of Vitamin C and Leukemia: In Vitro Update

Milardi¹,

Massai²,

Fioritoni³

et al. 2018

Myeloid Leukemia

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Vitamin C (ascorbic acid) is an essential nutrient with a number of beneficial effects on the human body. Although the majority of mammals can synthesize their own Vitamin C, humans and a few other species, do not produce it and depend on dietary sources for their Vitamin C supply. Among its many effects on cell function and metabolism, Vitamin C has shown, in vitro, a powerful anticancer effect against a number of human tumor cell lines, including myeloid leukemia. There are many different mechanistic explanations for the anticancer/anti-leukemic effects of Vitamin C and the aim of the present review is to illustrate these mechanisms, showing the results of some preliminary in vitro investigations, and outlining their potential clinical relevance.

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AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation

Cited by 77 publications

References 49 publications

Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells

Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

High Doses of Vitamin C and Leukemia: In Vitro Update

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