الفهرس 
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Abstract
Acute myeloid leukemia (AML) is a haematological disorder characterized by the aggregation and clonal proliferation of malignant blast cells of myeloid origin in peripheral blood and BM.
Numerous studies suggested that the disease might be caused by a genetic predisposition paired with variables of environmental origin such as heavy radiation exposure, infections, and chemical occupational toxins exposures.
Growing evidence suggested that various non-coding RNAs (ncRNAs) may serve as a connection between the genome and environment because they were linked to physiological and pathological processes. It became clear that different cancer etiologies were caused by variations in the noncoding genome as well as protein-coding mutations.
Small ncRNAs with less than 200 nucleotides and long ncRNAs with more than 200 nucleotides are the two basic groups into which noncoding RNAs are divided according to the transcript size.
LncRNAs have multiple modes of action, including involvement in controlling chromatin condensation, regulation of transcription, regulation of RNA splicing, controlling RNA stability, and promoting or inhibiting translation of mRNAs to proteins.
It has been reported that the dysregulation of lncRNAs occurs in numerous diseases, including cancers and affects tumor development and progression. Furthermore, research suggested that lncRNAs can be helpful as promising therapeutic, prognostic, and diagnostic targets in some malignancies.
LncRNA small nucleolar RNA host gene 5 (SNHG5), located on chromosome 6q, was reported to be strongly implicated in processes as cell differentiation, proliferation, and metastasis. The aberrant expression of SNHG5 had been reported in several human cancers including malignant melanoma, colorectal cancer, and gastric cancer.
LncRNA promoter of cyclin dependent kinase inhibitor 1A antisense DNA damage-activated RNA (PANDAR) has been implicated in chromosomal instability, and cancer progression. Many solid malignancies, including hepatocellular carcinoma, gastric cancer, and breast cancer, have been found to express PANDAR abnormally, but up till now there are limited studies about its expression in AML.
The aim of this study was to investigate the different expression patterns, prognostic significance of SNHG5 and PANDAR genes and their clinical significance in newly diagnosed adult Egyptian acute myeloid leukemia patients.
The current study was conducted on 100 subjects divided into two groups. Patients’ group which included 80 (49 male and 31 female) newly diagnosed adult acute myeloid leukemia patients and control group included 20 apparently healthy individuals matched age and sex. Patients who started treatment and patients who have other neoplasms were excluded from the study.
This study was conducted at the clinical pathology department, National Cancer Institute, Cairo University, Egypt, from 2019 to 2022. All peripheral blood and bone marrow samples were collected after written informed consent from participants before enrolment in the study. This study was approved by the ethical scientific committee of Benha University.
All patients underwent thorough clinical examination, extensive history taking, clinical examination, and laboratory tests, such as full blood picture, BM aspiration, cytogenetic study, immunophenotyping (IPT), and PCR for gene mutations as NPM1 and FLT3-ITD. Quantitative estimation of SNHG5 and PANDAR gene expression using quantitative real time PCR was performed to all participants in the study.
The Results revealed the following:
The studied patients demonstrated significantly higher expression of SNHG5 and PANDAR genes compared to the control group (P = 0.026 and < 0.001, respectively).
ROC analysis was performed for SNHG5 and PANDAR gene expression to distinguish AML patients from controls. For the SNHG5 gene, a significant area under the curve (AUC) was 0.672 (P-value = 0.026), with a 95% confidence interval ranging from 0.567 – 0.778, so it might act as a promising marker for differentiating AML patients from the control group. The best cutoff value was greater than 2.35, at which sensitivity was 45%, and specificity was 100%. The negative predictive value (NPV) was 27.9%, while the positive predictive value (PPV) was 100%.
On the other hand, a significant AUC was 0.790 (p < 0.001) for the PANDAR gene, with a 95% confidence interval ranging from 0.703 – 0.876, so it might act as a promising marker for differentiating AML patients from the control group. The best cutoff value was greater than 2.64, at which sensitivity and specificity were 64.6% and 100%, respectively. PPV for the PANDAR expression was 100%, while NPV was 41.7%.
Patients were classified according to the cutoff from ROC analysis of SNHG5 and PANDAR genes into low and high-expression groups. Patients with high SNHG5 gene expression demonstrated significantly higher median initial PB blast (65%) compared to those with low expression (49%) (P-value = 0.043), and a considerable difference was demonstrated regarding splenomegaly between high expression and low expression groups (P-value = 0.033). No significant differences were found regarding hepatomegaly, lymphadenopathy, IPT, FAB subtypes, and genetic risk groups.
Regarding the PANDAR gene, a significant difference was observed concerning splenomegaly between high-expression and low-expression groups (P-value = 0.006). In contrast, no significant differences were observed regarding hepatomegaly, lymphadenopathy, IPT, and FAB subtypes, and genetic risk groups.
Kaplan Meier analysis compared the overall survival (OS) and disease-free survival (DFS) according to SNHG5 gene expression. OS was significantly better in patients with low gene expression than those with high gene expression (Log-rank P = 0.004), so SNHG5 gene expression can be used as a predictor for OS. In contrast, DFS did not significantly differ according to SNHG5 gene expression (Log-rank P = 0.192).
Regarding PANDAR gene, no significant difference was detected between patients with high gene expression and those with low gene expression regarding OS and DFS (Log-rank P = 0.213 and 0.943, respectively).
An interesting finding in this study was that there was a significant positive correlation between PANDAR and SNHG5 gene expression in AML patients suggesting pathogenic role of SNHG5 and PANDAR in AML and they were good diagnostic marker in AML.
In conclusion, SNHG5 and PANDAR genes overexpression could be considered as diagnostic biomarkers for AML in Egyptian patients, and their downregulation may open a new hope for better therapeutic approaches. SNHG5 gene expression can be used as a predictor for OS but not DFS, while PANDAR gene expression has no impact on OS and DF