Clinical implications of genome-wide DNA methylation studies in acute myeloid leukemia

Li, Yan; Xu, Qingyu; Lv, Na; Wang, Lili; Zhao, Hongmei; Wang, Xiuli; Guo, Jing; Chen, Chongjian; Li, Yonghui; Yu, Li

doi:10.1186/s13045-017-0409-z

Cited by 33 publications

(42 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epigenetic dysregulation plays a major role in leukemogenesis [36][37][38][39]. Hypomethylating agents have been shown to be active in AML as a single agent as well as in combination regimens [40][41][42][43][44][45][46].…”

Section: Gilteritinib In Combination Regimensmentioning

confidence: 99%

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019

View full text Add to dashboard Cite

FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

show abstract

Section: Gilteritinib In Combination Regimensmentioning

confidence: 99%

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019

View full text Add to dashboard Cite

show abstract

“…Moreover, the epigenetic changes are reversible by small molecules and therapeutics that reactivate epigenetically silenced genes and improve outcomes of the disease (Table 5). 12,13 DNMT3A Mutations DNMT3A mutations, one of the most important epigeneticrelated alterations, are classified as the earliest and recurrent aberration in myeloid malignancies, occurring in 20-22% of adults with de novo AML (rare in children). Almost all CN-AML patients harbor at least a single point mutation in one of DNMT3A alleles and about 30-37% of them show DNMT3A loss-of-function mutations.…”

Section: Mutations In Epigenetic Genesmentioning

confidence: 99%

“…Based on the cytogenetic and molecular analysis and according to the risk stratification, AML genetic aberrations are placed into three categories; 1) Non-random chromosomal aberrations including balanced translocations, inversions, deletions, monosomies, and trisomies (Tables 2 and 3), 2) Multiple gene mutations (Table 4) and 3) Epigenetic alterations (Table 5). 6,[12][13][14] Actually, aberrations should occur in genes relevant for pathogenesis, ie, master transcription factor fusions (18% of cases), NPM1 (27% of cases), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloidtranscription genes (22%), cohesion complex genes (13%), and spliceosome complex genes (14%). 1,3,7 At the molecular level, AML is the consequence of collaboration between at least three broad classes of gene alterations (Table 6 & Figure 1).…”

mentioning

confidence: 99%

<p>Genetic Characterization and Risk Stratification of Acute Myeloid Leukemia</p>

Pourrajab¹,

Zare-Khormizi²,

Hashemi³

et al. 2020

CMAR

View full text Add to dashboard Cite

The most common acute leukemia in adults is acute myeloid leukemia (AML). The pathophysiology of the disease associates with cytogenetic abnormalities, gene mutations and aberrant gene expressions. At the molecular level, the disease manifests as changes in both epigenetic and genetic signatures. At the clinical level, two aspects of AML should be taken into account. First, the molecular changes occurring in the disease are important prognostic and predictive markers of AML. Second, use of novel therapies targeting these molecular changes. Currently, cytogenetic abnormalities and molecular alterations are the common biomarkers for the prognosis and choice of treatment for AML. Finding a panel of multiple biomarkers is a crucial diagnostic step for patient classification and serves as a prerequisite for individualized treatment strategies. Furthermore, the most important way of identifying relevant targets for new treatment approaches is defining specific patterns or a spectrum of driver gene mutations occurring in AML. Then, an algorithm can be established by the use of several biomarkers, to be used for personalized medicine. This review deals with molecular alterations, risk stratification, and relevant therapeutic decision-making in AML.

show abstract

“…Abnormal promoter methylation of many genes is one of the most common and the most studied epigenetic alteration, which regulates gene expression . Recently, several epigenetic biomarkers have provided helpful information in evaluating prognosis and predicting therapeutic response for the patients with AML . Therefore, identifying novel genetic abnormalities and epigenetic alterations may be useful to identify the disease risks and optimize treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Zhang

Zhou

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

The present study was aimed to investigate SCIN expression as well as promoter methylation and further explore their clinical relevance in acute myeloid leukemia (AML) patients. Real-time quantitative PCR was carried out to detect the expression level of SCIN in 119 AML patients and 37 healthy controls. Real-time quantitative methylation-specific PCR and bisulfite sequencing PCR were carried out to detect SCIN promoter methylation levels in 103 AML patients and 29 controls. As compared with controls, the level of SCIN transcript was significantly down-regulated in AML patients (P = 0.001), and the level of methylated SCIN promoter was significantly higher in AML patients (P = 0.001). Moreover, the level of promoter methylation was weakly negatively correlated with SCIN expression in AML patients (R = -0.265, P = 0.027). Demethylation of SCIN promoter by 5-aza-2'-deoxycytidine could restore its expression in leukemic cell line THP1. The age of SCIN patients was significantly higher and C/EBPA mutation was significantly less than SCIN patients (P = 0.039 and 0.038, respectively). Moreover, the rate of complete remission (CR) of SCIN patients was significantly lower than SCIN patients (P = 0.009). Kaplan-Meier analysis showed that low SCIN expression was associated with shorter overall survival (P = 0.036). Cox regression analysis demonstrated low SCIN expression was an independent poor prognostic factor (P = 0.047). Furthermore, SCIN expression was restored in those patients who achieved CR after induction therapy (P = 0.003). These findings indicate that decreased SCIN expression associated with its promoter methylation is a valuable biomarker for predicting adverse prognosis in AML patients.

show abstract

Clinical implications of genome-wide DNA methylation studies in acute myeloid leukemia

Cited by 33 publications

References 93 publications

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

<p>Genetic Characterization and Risk Stratification of Acute Myeloid Leukemia</p>

Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Contact Info

Product

Resources

About