Hypomethylation‐mediated H19 overexpression increases the risk of disease evolution through the association with BCR‐ABL transcript in chronic myeloid leukemia

Abstract

Previous study has revealed that H19 expression is required for efficient tumor growth induced by BCR-ABL in chronic myeloid leukemia (CML). Herein, we further determined H19 expression and its clinical implication in patients with CML. H19 expression and methylation were detected by real-time quantitative PCR and real-time quantitative methylation-specific PCR, and then clinical implication of H19 expression was further analyzed. H19 expression was significantly up-regulated in CML patients (p < 0.001). H19 expression with an area under receiver operating characteristic curve value of 0.824 might serve as a promising biomarker in distinguishing CML patients from controls. The patients with high H19 expression had a tendency of higher white blood cells and BCR-ABL transcript than those with low H19 expression. H19 overexpression occurred with the higher frequency in blast crisis stage (11/11, 100%), lower in accelerated phase (3/5, 60%), and chronic phase (42/62, 66%) stages. Moreover, paired patients during disease progression with increased BCR-ABL transcript also showed a significant upregulation of H19 expression. Meanwhile, H19 expression was decreased in follow-up patients who achieved complete molecular remission after tyrosine kinase inhibitors-based therapy. Epigenetic studies showed that H19 differentially methylated region/imprinting control region (DMR/ICR) was hypomethylated and associated with H19 expression in CML patients. Moreover, demethylation of H19 DMR/ICR reactivated H19 expression in K562 cells. Collectively, H19 overexpression, a frequent event in CML, was associated with higher BCR-ABL transcript involving in disease progression. Moreover, H19 DMR/ICR hypomethylation in CML may be one of the mechanisms mediating H19 overexpression.

H19 overexpression promotes leukemogenesis and predicts unfavorable prognosis in acute myeloid leukemia

“…Strong evidence has proved that aberrant H19 DMR/ICR methylation by controlling CTCF6 binding sites led to LOI of IGF2 / H19 and finally resulted in abnormal expression of IGF2 / H19 in diverse human cancers [ 36 – 38 ]. Moreover, our previous study showed that H19 DMR/ICR demethylation resulted in upregulation of H19 expression in leukemic cell line K562 [ 39 ]. Herein, we also investigated the pattern of H19 DMR/ICR methylation in AML patients and determined the association with H19 expression.…”

Arresting of miR-186 and releasing of H19 by DDX43 facilitate tumorigenesis and CML progression

“…5e, f ). Moreover, clinical sample analysis found H19 overexpression was associated with promoter hypomethylation and was upregulated during CML progression [ 26 ]. These results indicated that DDX43 may regulate the expression of H19 through demethylation.…”

“…H19 has been revealed to be upregulated in various carcinomas and to play important roles in the occurrence, development, metastasis, and prognosis of tumors [ 27 – 30 ]. Our previous study indicated that H19 expression, associated with its promoter methylation, was significantly upregulated in CML patients, and its expression increased as disease progressed [ 26 ]. H19 acts mainly through two ways: first, miR-675, encoded by the first exon of H19, regulates the relevant tumor suppressor genes [ 28 , 31 – 33 ]; second, the total length of H19 combines with microRNAs or related proteins to regulate their functions [ 28 , 34 , 35 ].…”

Establishment and molecular characterization of decitabine‐resistant K562 cells

“…[31][32][33][34] Our previous study revealed that H19 expression level, associated with its promoter methylation status, was significantly upregulated in CML patients involving in disease progression. 35 Also, H19 was identified to be upregulated by DDX43 through demethylation related to CML progression. 20 Among AML, H19 overexpression correlated with poor chemotherapy response and shorter overall survival 36 Taken together, we deduced that H19 may play a role in drug resistance during leukemogenesis.…”