Abstract
Introduction: Acute myeloid leukemia (AML) is a malignant clonal proliferative disease originating from hematopoietic stem cells, characterized by anemia, hemorrhage, infection and organ infiltration. Most of the patients had poor prognosis and the molecular mechanism of AML is not clear. Therefore, it is urgent to find new molecular markers and therapeutic targets for AML. Long noncoding RNAs (lncRNAs) are a class of RNAs, which are longer than 200nt and without the ability of encoding functional proteins [A. Fatica et al., 2014]. Accumulating studies have found that lncRNAs play an important role in the development of hematological tumors, especially in AML [Huang J et al., 2014; Xing C-y et al., 2015]. In order to investigate the mechanism of lncRNAs in AML, we screened the differentially expressed RNAs in 5 AML patients and 5 IDA controls by microarray (GSE103828), and lncRNA AC092580.4 was verified markedly low expressed in AML (fold change=15.25, P= 0.0002). Then, We further explored the relationship between the expression levels of AC092580.4 and the clinical characteristics and prognosis of AML.
Methods: Bone marrow (BM) samples from patients with AML and iron deficiency anemia (IDA) were collected and qRT-PCR was performed to verify the expression levels of AC092580.4 in AML patients and controls. The Receiver Operating Characteristic (ROC) was established to analyze whether AC092580.4 could be used as a bio-marker for newly diagnosed AML patients. The clinical data, including age, gender, percentage of blast cells in BM, chromosome and gene abnormalities, risk stratification, white blood cell counts and overall survival were collected. The correlation between the expression levels of AC092580.4 and clinical characteristics were analyzed by SPSS22.0.
Results: The expression levels of AC092580.4 in newly diagnosed AML (n=83) was significantly lower (Figure A) than IDA (n=24) (p < 0.0001). The ROC (Figure B) was established and the area under curve was 0.868 (p < 0.001, CI: 0.780 - 0.957), which indicated that AC092580.4 could be used as an effective index to distinguish the newly diagnosed AML from the controls. Clinical data were collected from 83 newly diagnosed AML patients, 67% was the mean value of the percentage of blast cells in BM . It was found that the expression levels of AC092580.4 were significantly different between the high (≥67%) and low(<67%) percentage of blast cells (p=0.001), high white blood cell group (WBC≥100×109/L) and non high white blood cell group (WBC<100×109/L) (p=0.021). There was no significant difference of the expression levels in the patients with favourable, intermediate and adverse according to Diagnosis and management of AML in adults 2017 ELN recommendations from an international expert panel (p=0.328). The overall survival rate (Figure C) analysis showed that AML patients with high expression levels of AC092580.4 have a better prognosis than low expression group (p=0.018), which indicated that AC092580.4 may be used as an effective index to predict prognosis. To explore the mechanism of AC092580.4 in AML, we obtained sequencing data of 151 adult AML patients from The Cancer Genome Atlas (TCGA) (https://cancergenome.nih.gov/abouttcga/). The correlation coefficient between AC092580.4 and coding gene was estimated by Pearson correlation method. The results showed that the correlation coefficient between GATA3 and AC092580.4 (r = 0.679, P <0.05) was the most significant one among 27338 transcripts (Figure D). Therefore, we hypothesize that AC092580.4 may play an important role in the pathogenesis of AML by interacting with GATA3. GATA3 is a transcription factor of GATA family. While promoting the development of Th2 cells, it can also inhibit the Th1 polarization of Th cells, and eventually lead to higher expression of Th2, which may lead to the occurrence of tumor.
Conclusions: Our study sheds light on a novel lncRNA AC092580.4 in AML, and provides its possible functional mechanism preliminary. Whether it can be used as a new powerful therapeutic target for AML treatment remains to be further studied.
No relevant conflicts of interest to declare.
