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

Abstract

BackgroundThe long non-coding RNA H19 plays a crucial role in solid tumor initiation and progression. However, the potential role of H19 and its clinical significance in acute myeloid leukemia (AML) remain largely elusive.MethodsH19 expression was detected by qPCR, and clinical significance in AML patients was further analyzed. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data for AML were used as validation cohorts. The roles of H19 in cell proliferation and apoptosis were determined by cell proliferation assay and flow cytometry analysis.ResultsH19 expression was significantly increased in AML patients but not associated with embedded miR-675 expression. Moreover, H19 overexpression was not dependent on the methylation pattern in H19 differentially methylated region/imprinting control region. Strong association was observed between H19 overexpression and patients’ characteristics including sex, higher white blood cells, older age, and intermediate karyotype, FLT3-ITD, and DNMT3A mutations. In addition, H19 overexpression correlated with lower complete remission (CR) rate and shorter overall survival, and further confirmed by multivariate analyses. Importantly, the prognostic effect of H19 expression was validated by TCGA and GEO data. In the follow-up of patients, H19 expression in CR phase was lower than diagnosis time and returned at relapse time. Loss-of-function experiments showed that H19 exhibited anti-proliferative and pro-apoptotic effects in leukemic cell HL60. Furthermore, H19 expression was positively correlated with potential downstream gene ID2 in AML.ConclusionsOur findings revealed that methylation-independent H19 was a prognostic and predictive biomarker in AML, and H19/ID2 played crucial roles in leukemogenesis with potential therapeutic target value.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0486-z) contains supplementary material, which is available to authorized users.

Establishment and molecular characterization of decitabine‐resistant K562 cells

“…11,21 Therefore, it is important to illuminate the resistance mechanism and to overcome H19 is a long chain non-coding RNA with length of 2.3 kb. 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. [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.…”

“…Real-time quantitative PCR (RQ-PCR) was conducted to evaluate the mRNA and miRNA expression levels in the DAC resistant cells as previously described using the primer sets (Table S1). [15][16][17][18][19]…”

“…Genomic DNA isolation, chemical modification, real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP) were performed as our previous study. 15,18…”

EZH2 dysregulation: Potential biomarkers predicting prognosis and guiding treatment choice in acute myeloid leukaemia

“…We found that EZH2 dysregulation was significantly associated with HOX gene family, THBS1, CDKN2B, PAX2 and H19, which was reported highly correlated with haematopoiesis and leukaemogenesis. [23][24][25][26][27] Moreover, for microRNAs, we observed that EZH2 expression was negatively correlated with several mi-croRNAs such as miR-21, miR-23a, miR-500, let-7a-3, miR-362, let-7e…”

“…The effect of HSCT on survival of AML patients among EZH2 low-and high-expressed groups. We found that EZH2 dysregulation was significantly associated with HOX gene family, THBS1, CDKN2B, PAX2 and H19, which was reported highly correlated with haematopoiesis and leukaemogenesis [23][24][25][26][27]. Survival was analysed though Kaplan-Meier analysis using Log-rank test between transplantation and chemotherapy in AML.…”