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5. Data from Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine

Author

Ohtani, Hitoshi, primary, Ørskov, Andreas D., primary, Helbo, Alexandra S., primary, Gillberg, Linn, primary, Liu, Minmin, primary, Zhou, Wanding, primary, Ungerstedt, Johanna, primary, Hellström-Lindberg, Eva, primary, Sun, Weili, primary, Liang, Gangning, primary, Jones, Peter A., primary, and Grønbæk, Kirsten, primary

Published
2023
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6. Supplementary Figures 1-10 from Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine

Author

Ohtani, Hitoshi, primary, Ørskov, Andreas D., primary, Helbo, Alexandra S., primary, Gillberg, Linn, primary, Liu, Minmin, primary, Zhou, Wanding, primary, Ungerstedt, Johanna, primary, Hellström-Lindberg, Eva, primary, Sun, Weili, primary, Liang, Gangning, primary, Jones, Peter A., primary, and Grønbæk, Kirsten, primary

Published
2023
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8. Supplementary Tables from Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine

Author

Ohtani, Hitoshi, primary, Ørskov, Andreas D., primary, Helbo, Alexandra S., primary, Gillberg, Linn, primary, Liu, Minmin, primary, Zhou, Wanding, primary, Ungerstedt, Johanna, primary, Hellström-Lindberg, Eva, primary, Sun, Weili, primary, Liang, Gangning, primary, Jones, Peter A., primary, and Grønbæk, Kirsten, primary

Published
2023
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15. Abstract CT121: A Phase II trial of guadecitabine (G) plus atezolizumab (A) in patients with metastatic urothelial carcinoma (UC) progressing after initial checkpoint inhibitor therapy

Author

Plimack, Elizabeth R., primary, Campbell, Kerry, additional, Issa, Jean-Pierre J., additional, Hahn, Noah M., additional, Quinn, David I., additional, Jang, Hyo Sik, additional, Hostetter, Galen, additional, Nichols, Peter W., additional, Chung, Woonbok, additional, Madzo, Jozef, additional, Ohtani, Hitoshi, additional, Shen, Hui, additional, Hinoue, Toshinori, additional, Baylin, Stephen B., additional, and Jones, Peter A., additional

Published
2021
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21. Activation of a subset of evolutionarily young transposable elements and innate immunity are linked to clinical responses to 5-azacytidine

Author

Ohtani, Hitoshi, Ørskov, Andreas D., Helbo, Alexandra S., Gillberg, Linn, Liu, Minmin, Zhou, Wanding, Ungerstedt, Johanna, Hellström-Lindberg, Eva, Sun, Weili, Liang, Gangning, Jones, Peter A., Grønbæk, Kirsten, Ohtani, Hitoshi, Ørskov, Andreas D., Helbo, Alexandra S., Gillberg, Linn, Liu, Minmin, Zhou, Wanding, Ungerstedt, Johanna, Hellström-Lindberg, Eva, Sun, Weili, Liang, Gangning, Jones, Peter A., and Grønbæk, Kirsten

Abstract

The DNA methyltransferase inhibitors (DNMTi) 5-azacyti-dine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here, we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacy-tidine) elicit an immune response, which may be important for patient's responses to DNMTi.

Published
2020

22. Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine

Author

Ohtani, Hitoshi, primary, Ørskov, Andreas D., additional, Helbo, Alexandra S., additional, Gillberg, Linn, additional, Liu, Minmin, additional, Zhou, Wanding, additional, Ungerstedt, Johanna, additional, Hellström-Lindberg, Eva, additional, Sun, Weili, additional, Liang, Gangning, additional, Jones, Peter A., additional, and Grønbæk, Kirsten, additional

Published
2020
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26. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment:Normalization of plasma vitamin C induces epigenetic changes

Author

Gillberg, Linn, Ørskov, Andreas D., Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob W., Rapin, Nicolas, Mogensen, Johanne B., Liu, Minmin, Dufva, Inge H., Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter A., Grønbæk, Kirsten, Gillberg, Linn, Ørskov, Andreas D., Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob W., Rapin, Nicolas, Mogensen, Johanne B., Liu, Minmin, Dufva, Inge H., Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter A., and Grønbæk, Kirsten

Abstract

BACKGROUND: Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). RESULTS: We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 μM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 μM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 μM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041). CONCLUSIONS: Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively register

Published
2019

27. Abstract 3092: Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine

Author

Ohtani, Hitoshi, primary, Ørskov, Andreas D., additional, Helbo, Alexandra S., additional, Gillberg, Linn, additional, Liu, Minmin, additional, Zhou, Wanding, additional, Ungerstedt, Johanna, additional, Hellstrom-Lindberg, Eva, additional, Sun, Weili, additional, Liang, Gangning, additional, Jones, Peter A., additional, and Grønbæk, Kirsten, additional

Published
2019
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29. Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI‐110) in Hepatocellular Carcinoma

Author

Liu, Minmin, primary, Zhang, Lian, additional, Li, Hongtao, additional, Hinoue, Toshinori, additional, Zhou, Wanding, additional, Ohtani, Hitoshi, additional, El‐Khoueiry, Anthony, additional, Daniels, John, additional, O'Connell, Casey, additional, Dorff, Tanya B., additional, Lu, Qianjin, additional, Weisenberger, Daniel J., additional, and Liang, Gangning, additional

Published
2018
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38. Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine.

Author

Minmin Liu, Ohtani, Hitoshi, Wanding Zhou, Due Ørskov, Andreas, Charlet, Jessica, Zhang, Yang W., Hui Shen, Baylin, Stephen B., Gangning Liang, Grønbæk, Kirsten, and Jones, Peter A.

Subjects
*EPIGENETICS, *DNA methyltransferases, *PHYSIOLOGICAL effects of vitamin C, *VITAMIN C deficiency, *DEOXYCYTIDINE
Abstract

Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFNinducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis. [ABSTRACT FROM AUTHOR]

Published
2016
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44. APOBEC3Hpolymorphisms and susceptibility to HIV-1 infection in an Indian population

Author

Naruse, Taeko K, Sakurai, Daisuke, Ohtani, Hitoshi, Sharma, Gaurav, Sharma, Surendra K, Vajpayee, Madhu, Mehra, Narinder K, Kaur, Gurvinder, and Kimura, Akinori

Abstract

Human APOBEC3H (A3H) is a member of APOBEC cytidine deaminase family intensively constraining the HIV-1 replication. A3H is known to be polymorphic with different protein stability and anti-HIV-1 activity in vitro. We recently reported that A3H haplotypes composed of two functional polymorphisms, rs139292 (N15del) and rs139297 (G105R), were associated with the susceptibility to HIV-1 infection in Japanese. To confirm the association of A3H and HIV-1 infection in another ethnic group, a total of 241 HIV-1-infected Indian individuals and ethnic-matched 286 healthy controls were analyzed for the A3H polymorphisms. The frequency of 15del allele was high in the HIV-1-infected subjects as compared with the controls (0.477 vs 0.402, odds ratio (OR)=1.36, P=0.014). Haplotype analysis showed that the frequencies of 15del–105R was high (0.475 vs 0.400, OR=1.36, permutation P=0.037) in the HIV-1-infected subjects, confirming the association of A3H polymorphisms with the susceptibility to HIV-1 infection.

Published
2016
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45. MOESM1 of Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes

Author

Gillberg, Linn, Ørskov, Andreas, Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob, Rapin, Nicolas, Mogensen, Johanne, Minmin Liu, Dufva, Inge, Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter, and Grønbæk, Kirsten

Subjects
hemic and lymphatic diseases, 3. Good health
Abstract

Additional file 1: Supplementary information. Supplementary materials and methods. Table S1. Molecular and epigenetic features of the included MDS, CMML and AML patients randomized for either vitamin C or placebo supplementation. Table S2. Mutations in DNMT3A, IDH2 and TET2 in the enrolled MDS, CMML and AML patients. Table S3. Plasma vitamin C (vitC) concentration differentials between baseline (Pre vitC, C1D5, C2D1) and after short-term (Initial vitC, 4 d, C2D5) and longer-term (Stable vitC, 4–8 weeks, C3D1, C3D5, C3D28) supplementation of either 500 mg of vitamin C or placebo tablets. Table S4. Associations between plasma levels of vitamin C and plasma levels of ferritin, iron, and transferrin during each treatment cycle/treatment day (CxDx). Table S5. A) Associations between plasma levels of vitamin C at baseline and IPSS–R score (MDS prognostic risk category), haemoglobin, blast percentage, number of blood transfusions, and WHO diagnosis. B) Associations between baseline levels of global 5mC or 5hmC/5mC and plasma vitamin C level or age. Fig S1. Plasma vitamin C levels at baseline for patients with and without mutations in the DNA methylation regulators TET2 (A; n = 7), DNMT3A (B; n = 5) and IDH2 (n = 2). Fig S2. Plasma levels of iron, ferritin, and transferrin in all participants in the placebo and vitamin C arm, respectively, as a function of treatment cycle and day.

46. MOESM1 of Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes

Author

Gillberg, Linn, Ørskov, Andreas, Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob, Rapin, Nicolas, Mogensen, Johanne, Minmin Liu, Dufva, Inge, Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter, and Grønbæk, Kirsten

Subjects
hemic and lymphatic diseases, 3. Good health
Abstract

Additional file 1: Supplementary information. Supplementary materials and methods. Table S1. Molecular and epigenetic features of the included MDS, CMML and AML patients randomized for either vitamin C or placebo supplementation. Table S2. Mutations in DNMT3A, IDH2 and TET2 in the enrolled MDS, CMML and AML patients. Table S3. Plasma vitamin C (vitC) concentration differentials between baseline (Pre vitC, C1D5, C2D1) and after short-term (Initial vitC, 4 d, C2D5) and longer-term (Stable vitC, 4–8 weeks, C3D1, C3D5, C3D28) supplementation of either 500 mg of vitamin C or placebo tablets. Table S4. Associations between plasma levels of vitamin C and plasma levels of ferritin, iron, and transferrin during each treatment cycle/treatment day (CxDx). Table S5. A) Associations between plasma levels of vitamin C at baseline and IPSS–R score (MDS prognostic risk category), haemoglobin, blast percentage, number of blood transfusions, and WHO diagnosis. B) Associations between baseline levels of global 5mC or 5hmC/5mC and plasma vitamin C level or age. Fig S1. Plasma vitamin C levels at baseline for patients with and without mutations in the DNA methylation regulators TET2 (A; n = 7), DNMT3A (B; n = 5) and IDH2 (n = 2). Fig S2. Plasma levels of iron, ferritin, and transferrin in all participants in the placebo and vitamin C arm, respectively, as a function of treatment cycle and day.

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