High levels of global DNA methylation are an independent adverse prognostic factor in a series of 90 patients with de novo myelodysplastic syndrome

Calvo, Xavier; Nomdedéu, Meritxell; Navarro, Alfons; Tejero, Rut; Costa, Dolors; Muñoz, Concha; Pereira, Arturo; Peña, Oscar; Risueño, Ruth M.; Monzó, Mariano; Esteve, Jordi; Nomdedeu, Benet

doi:10.1016/j.leukres.2014.04.015

Cited by 19 publications

(13 citation statements)

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“…Both of these findings suggest a link between iron and leukemogenesis. Concerning the mechanism, DNA methylation is considered to be associated with the pathogenesis and exacerbation of MDS [23][24][25][26][27]. In this study, we first demonstrated that iron overload activated the ACO1-IDH pathway in the TCA cycle and led to increased 2-HG activity, which induced DNA methylation, a critical epigenetic aberration process.…”

Section: Discussionmentioning

confidence: 69%

“…α-KG acts as a substrate of the TCA cycle, whereas it is utilized in many other reactions including DNA demethylation [20,21]. Recently, IDH mutation and the up-regulation of DNA methylation were also predicted to be independent prognosis factors in patients with MDS [22][23][24][25][26][27]. Therefore, the mechanism of aberrant DNA methylation in patients with MDS is to be elucidated further.…”

Section: Introductionmentioning

confidence: 99%

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Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

et al. 2016

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Iron overload remains a concern in myelodysplastic syndrome (MDS) patients. Iron chelation therapy (ICT) thus plays an integral role in the management of these patients. Moreover, ICT has been shown to prolong leukemia-free survival in MDS patients; however, the mechanisms responsible for this effect are unclear. Iron is a key molecule for regulating cytosolic aconitase 1 (ACO1). Additionally, the mutation of isocitrate dehydrogenase (IDH), the enzyme downstream of ACO1 in the TCA cycle, is associated with epigenetic abnormalities secondary to 2-hydroxyglutarate (2-HG) and DNA methylation. However, epigenetic abnormalities observed in many MDS patients occur without IDH mutation. We hypothesized that iron itself activates the ACO1-IDH pathway, which may increase 2-HG and DNA methylation, and eventually contribute to leukemogenesis without IDH mutation. Using whole RNA sequencing of bone marrow cells in iron-overloaded mice, we observed that the enzymes, phosphoglucomutase 1, glycogen debranching enzyme, and isocitrate dehydrogenase 1 (Idh1), which are involved in glycogen and glucose metabolism, were increased. Digital PCR further showed that Idh1 and Aco1, enzymes involved in the TCA cycle, were also elevated. Additionally, enzymatic activities of TCA cycle and methylated DNA were increased. Iron chelation reversed these phenomena. In conclusion, iron activation of glucose metabolism causes an increase of 2-HG and DNA methylation.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

et al. 2016

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“…Негативное влияние на ОВ при терапии азацити-дином оказывают аберрантный статус метилирования не менее 2 генов и высокий уровень глобального метили-рования, сложный кариотип с 3 и более хромосомными аберрациями, сохраняющаяся потребность в регулярных трансфузиях эритроцитной взвеси, мутационный статус гена ТР53 [22][23][24][25][26][27]. Вместе с тем, несмотря на широкий спектр предлагаемых предикторов, следует признать, что прогностическая значимость большинства из них, и прежде всего молекулярно-генетических аберраций, нуждается в дополнительном подтверждении [19].…”

Section: Discussionunclassified

Hematological Improvement is a Favorable Response to Azacitidine in Patients with Acute Myeloid Leukemias and Myelodysplastic Syndromes

Кострома¹,

Грицаев²,

Karyagina³

et al. 2015

Clin oncohematol

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11 ФГБУ «Российский научно-исследовательский институт гема-тологии и трансфузиологии» ФМБА РФ, ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024 2 ГБУЗ «Городская больница № 15», ул. Авангардная, д. 4, Санкт-Петербург, Российская Федерация,198205 3 Александровская городская больница № 17, пр-т Солидарности, д. 4, Санкт-Петербург, Российская Федерация, 193312 РЕФЕРАТ Цель. Поиск вариантов ответа на лечение азацитидином, связанных с улучшением показателей общей выживае-мости (ОВ) больных с острыми миелоидными лейкозами (ОМЛ) и миелодиспластическими синдромами (МДС). Методы. Проведен ретроспективный анализ историй бо-лезни 14 больных ОМЛ и 13 больных МДС в возрасте 39-84 года, которым назначался азацитидин по 75 мг/м 2 под-кожно в течение 7 последовательных дней каждые 28 дней. Эффективность оценивали по модифицированным крите-риям IWG 2006 г. ОВ рассчитывали от даты начала терапии азацитидином. Результаты. Число проведенных курсов было 2-25. Пол-ная ремиссия (ПР) достигнута у 6 (22,2 %) больных, вклю-чая 4 ОМЛ и 2 МДС. Костномозговая полная ремиссия (кмПР) констатирована у 1 (3,7 %) пациента с МДС. Ге-матологическое улучшение зафиксировано у 11 (40,7 %) больных, из которых 5 были с ОМЛ и 6 -с МДС. Общий ответ составил 66,7 % (18 из 27 больных). Не обнаруже-но связи эффективности терапии с возрастом, вариантом заболевания, длительностью предшествующего периода, исходными уровнями гемоглобина, лейкоцитов и тромбо-цитов, зависимостью от трансфузий эритроцитной взвеси и тромбоконцентрата. Терапия расценена как неэффек-тивная у 9 (33,3 %) больных. У 4 пациентов с ОМЛ и 3 -с МДС констатирована стабилизация с сохранением потреб-ности в трансфузии компонентов крови. У 2 больных от-мечено постепенное повышение числа бластных клеток в костном мозге. При сроке наблюдения 2-29 мес. медиана ОВ всех больных составила 11,5 мес. Медиана ОВ в группе ABSTRACTAim. To evaluate types of response to azacitidine associated with improvement of overall survival (OS) rates of patients with acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS). Methods. A retrospective analyses of medical records of 14 AML patients and 13 MDS patients at the age of 39 to 84 treated with azacitidine at a dose of 75 mg/m 2 subcutaneously for 7 subsequent days every 28 days was performed. The therapy effectiveness was evaluated according to modified 2006 IWG criteria. The OS was calculated beginning with the date of initiation of the azacitidine therapy. Results. From 2 to 25 azacitidine cycles was performed. Complete remission (CR) was achieved in 6 patients (22.2 %) including 4 AML and 2 MDS patients. Bone marrow remission (mCR) was diagnosed in 1 MDS patient (3.7 %). Hematological improvement was obtained in 11 patients (40.7 %) including 5 AML and 6 MDS patients. The overall response was 66.7 % (18 to 27 patients). There was no correlation between the therapy effectiveness and patients' age, disease type, duration of the previous period, baseline hemoglobin, leukocytes, and platelets levels, and dependence on tra...

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“…Patients show aberrant methylation of cytosine residues in CpG sequences [2,3] and a DNA hypermethylation profile, particularly in promoter regions of tumor suppressor genes [4,5]. These genetic alterations can impact patients' survival [6][7][8][9][10], yet whether they can also influence their response to azacitidine/decitabine treatment has not been clearly elucidated.…”

Section: Introductionmentioning

confidence: 99%

Mutations in DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes

Cedena¹,

Rapado²,

Santos‐Lozano³

et al. 2017

Leukemia Research

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We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio .09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n=815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes: ASXL1, CBL, EZH2, SF3B1, SRSF2, TET2, DNMT3A, IDH1/2 and TP53. TET2 mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR: 1.67, 95%CI: 1.14-2.44; p=0.01). In conclusion, mutations in the DNA methylation pathway, especially TET2 mutations, and low number of total mutations are associated with a better response to azacitidine. www.impactjournals.com/oncotarget/[

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High levels of global DNA methylation are an independent adverse prognostic factor in a series of 90 patients with de novo myelodysplastic syndrome

Cited by 19 publications

References 44 publications

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Hematological Improvement is a Favorable Response to Azacitidine in Patients with Acute Myeloid Leukemias and Myelodysplastic Syndromes

Mutations in DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes

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