Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia

Yamato, Genki; Kawai, Tomoko; Shiba, Norio; Ikeda, Junji; Hara, Yusuke; Ohki, Kentaro; Tsujimoto, Shin‐ichi; Kaburagi, Taeko; Yoshida, Kenichi; Shiraishi, Yuichi; Miyano, Satoru; Kiyokawa, Nobutaka; Tomizawa, Daisuke; Shimada, Akira; Sotomatsu, Manabu; Arakawa, Hirokazu; Adachi, Souichi; Taga, Takashi; Horibe, Keizo; Ogawa, Seishi; Hata, Kenichiro; Hayashi, Yasuhide

doi:10.1182/bloodadvances.2021005381

Cited by 11 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor suppressor gene methylation is one of the important links in the occurrence of malignant neoplastic diseases and substantially regulates the occurrence and development of malignant neoplastic diseases [ 22 – 24 ]. Detection of the methylation level of specific genes is one of the important ways to monitor the evolution and outcome of malignant neoplastic diseases [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Hua

Wang

et al. 2022

Applied Bionics and Biomechanics

View full text Add to dashboard Cite

Purpose. Abnormal methylation of Grainyhead-like 2 (GRHL2) is associated with a substantial role in the malignant phenotype of tumor patients. Our present research is aimed at studying the abnormal expression of GRHL2 and the association of methylation in patients with acute leukemia and its relationship with prognosis. Materials and Methods. We used quantitative real-time polymerase chain reaction (qRT-PCR) for detecting the aberrant expression level of GRHL2 in 60 patients with acute leukemia and 60 normal controls. We analyzed the significant correlation between the expression level of GRHL2 with clinicopathological features and patients’ prognosis in acute leukemia using the corresponding statistical methods. Secondly, we employed qRT-PCR and Western blotting to detect the mRNA and protein levels of GRHL2 in leukemia cell lines. Next, we used methylation-specific polymerase chain reaction (MSP) technology for detecting the methylation of GRHL2 in clinical samples with acute leukemia and cell lines. Then we investigated the demethylating effect of arsenic trioxide and 5-azacitidine on the mRNA and protein expression levels of GRHL2 in cell lines of acute leukemia. Finally, we studied the effects of arsenide trioxide and 5-azacitidine on the proliferation of leukemia cells and the TGF-β signaling pathway. Results. We found a lower level of GRHL2 expression not only in acute leukemia patients but also in cell lines when compared with normal controls. At the same time, the expression level of GRHL2 in patients with acute leukemia was significantly correlated with leukocyte count, platelet count, and cytogenetic risk grouping. In addition, the lower GRHL2 expression group showed a significantly lower overall survival rate in acute leukemia patients than that of patients with a higher GRHL2 expression group. Univariate and multivariate analyses revealed that the expression of GRHL2 is an independent risk factor in acute leukemia patients. The methylation level of the GRHL2 promoter region in acute leukemia patients and cell lines was significantly higher than the normal control group, and we found the elevated mRNA and protein levels of GRHL2 in acute leukemia cell lines after the use of the demethylation drug arsenic trioxide and 5-azacitidine. At the same time, arsenide trioxide and 5-azacitidine are associated with the inhibition of cellular proliferation of acute leukemia cells and also promote the elevated expression of TGF-β signaling pathway-linked proteins, including TGF-β, Smad2, Smad3, and Smad4. Conclusion. Increased expression and methylation level of GRHL2 are closely associated with the prognosis and malignant phenotype of acute leukemia patients and play an irreplaceable role in the occurrence and development of patients with acute leukemia.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Detection of the methylation level of specific genes is one of the important ways to monitor the evolution and outcome of malignant neoplastic diseases [25]. Acute leukemia is a common hematological malignancy in adults.…”

Section: Discussionmentioning

confidence: 99%

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

Hua

Wang

et al. 2022

Applied Bionics and Biomechanics

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“… 66 Limited studies of methylation status in children and inadequate data regarding the efficacy of azacitidine in children AML have restricted its application. 67 , 68 Moreover, recruitment of patients for maintenance studies has always been difficult. A study by Burnett et al 69 showed that only 27% of older patients who were initially enrolled were randomly assigned for maintenance treatment.…”

Section: Discussionmentioning

confidence: 99%

Homoharringtonine-Based Induction Regimen Improved the Remission Rate and Survival Rate in Chinese Childhood AML: A Report From the CCLG-AML 2015 Protocol Study

Gao

Liu

et al. 2023

JCO

View full text Add to dashboard Cite

PURPOSE Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML. PATIENTS AND METHODS This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years. RESULTS We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% v 73.9%, P = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm ( P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm ( P = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, P = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, P = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, P = .336). CONCLUSION HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

show abstract

“…Various forms of cancer such as colon, breast, liver, bladder, oesophageal, prostate, and bone cancers, have been reported with aberrant DNA methylation of imprinted sites [8] . Multiple omics-based research studies have also revealed that a variety of malignancies, including hepatocellular carcinoma [9] , glioblastoma, breast cancer, squamous cell lung cancer, thyroid carcinoma, and leukemia [10] , have diverse DNA methylation patterns. Moreover, DNMT mutations, various DNMT expression levels, dysregulation of TETs, and frequent observations of cancer, point towards a strong association between DNA methylation and cancer [11] .…”

Section: Introductionmentioning

confidence: 99%