الفهرس 
Acute myeloid leukemiaOnly 14 pages are availabe for public view
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Abstract
There is growing evidence of the crucial role of long non-coding RNAs (lncRNAs), a novel class of gene expression regulators, in cancer initiation, development and progression. LncRNAs are emerging as important molecular players in multiple cancers, and deregulated lncRNAs expression has been shown to hold crucial triggers of the pathogenesis of numerous hematological malignancies. Several lncRNAs have been demonstrated to play a critical role in the tumorigenesis of acute myeloid leukemia (AML), and altered expression of certain lncRNAs has been recognized as a potential prognostic marker in AML patients. Colorectal neoplasia differentially expressed (CRNDE), an intergenic lncRNA, has been demonstrated to be upregulated in various neoplasms, and its overexpression has been found to be associated with poor prognosis in patients with a variety of malignancies, however, its utility as a prognostic marker in AML has not yet been well studied. Aldehyde oxidase 2 pseudogene (AOX2P), a pseudogene-derived lncRNA, has been shown to be overexpressed in pediatric AML patients, nevertheless, it remains unclear whether AOX2P expression can affect the clinical outcome of AML. Here, we sought to determine whether the expression of the lncRNAs CRNDE and AOX2P is associated with clinicopathological features, cytogenetic aberrations, recurrent mutations and treatment response, as well as outcome of adults with de novo AML.
Patients and methods
A total of 200 newly diagnosed adult patients fulfilling the diagnostic criteria of de novo AML who were referred to the outpatient clinics of the Hematology unit, National Cancer Institute, Cairo University, Cairo, Egypt from December 2017 to July 2019 were recruited in the present study. In addition, peripheral blood samples from 50 age- and gender-matched healthy volunteers with no medical history of hematological disorders were included as controls.
Diagnosis and classification of the patients were based on the World Health Organization (WHO) and French-American-British (FAB) criteria, respectively. Risk group assignment at diagnosis was based on cytogenetic and molecular genetic findings as defined by the European Leukemia Net (ELN) recommendations.
Morphological and immunophenotypic characterization as well as cytogenetics and molecular genetic testing of samples from AML patients were performed according to standardized methods.
The expression levels of lncRNAs CRNDE and AOX2P were determined in diagnostic pretreatment leukemic blood samples using quantitative real-time polymerase chain reaction (qRT-PCR).
Results
CRNDE expression was significantly upregulated in all subgroups of patient samples when compared with normal control samples. Likewise, AOX2P was overexpressed in patient samples when compared with normal control samples.
There was a remarkable difference in CRNDE expression among the patient subgroups, with the highest CRNDE expression observed among patients with t(15;17) AML, followed by those with CN-AML, whereas the lowest CRNDE expression was found in non-t(15;17) CA-AML patients. In contrast, no significant difference in AOX2P expression was observed among the three patient subgroups.
High CRNDE expression status was associated with shorter EFS in the entire series of AML as well as in the CN-AML and non-t(15;17) CA-AML subsets, but not in the subgroup of t(15;17) AML. On the other hand, there was no significant difference in terms of EFS between patients with high AOX2P expression and those with low expression neither in the whole cohort of AML nor in the patient subgroups.
High CRNDE expression status was associated with inferior OS in the whole cohort of AML and in the subgroup of t(15;17) AML, but neither in the CN-AML nor in the non-t(15;17) CA-AML subset. On the other hand, OS didn’t differ significantly between patients with high AOX2P expression and those with low expression neither in the whole cohort of AML nor in the patient subgroups.
Multivariable analysis identified high CRNDE expression as an independent adverse prognostic marker associated with lower probability of attaining CR in the whole cohort of AML, but not in the patient subgroups. Moreover, high AOX2P expression was identified as an independent prognostic factor associated with lower possibility of CR achievement in the CN-AML and non-t(15;17) CA-AML subgroups.
Neither CRNDE nor AOX2P expression had a significant influence on EFS, neither in the whole cohort nor in the patient subgroups.
In multivariable analysis, high CRNDE expression was identified as an independent prognostic factor for inferior OS in the whole cohort of AML. On the other hand, AOX2P expression had no significant influence on OS, neither in the whole cohort nor in the patient subgroups.
Thirty-three miRNA families were identified as potential targets for AOX2P, whereas 30 miRNA families were identified as potential targets for CRNDE. Interestingly, 15 miRNA families were identified as targets for both AOX2P and CRNDE.
IPA of CRNDE led to the identification of 50 genes in the CRNDE-coding gene network that have been experimentally observed and/or highly predicted to be associated with one or more of the predetermined IPA ‘Functions and Diseases’.
CRNDE-coding gene network analysis revealed that 11 genes in the AML tumorigenesis-CRNDE pathway are involved in the canonical pathway for AML signaling.