Altered expression of imprinted genes in patients with cytogenetically normal‑acute myeloid leukemia: Implications for leukemogenesis and survival outcomes
- Authors:
- Published online on: October 5, 2023 https://doi.org/10.3892/mco.2023.2690
- Article Number: 94
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Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder characterized by genetic alterations in precursor cells within the bone marrow (BM), leading to the proliferation of neoplastic clonal myeloid stem cells (1). AML presents a considerable global health burden, with ~500 new cases in adults annually in Taiwan alone (2). As the most prevalent form of acute leukemia in adults, AML accounts for the highest proportion of leukemia-related deaths (3). The dysregulation of transcription factors and signaling pathways in hematopoiesis contributes to the development of malignant phenotypes such as AML and myelodysplastic syndromes (MDS), ultimately leading to the formation of leukemic stem cells (4).
Prognostic stratification in AML is predominantly based on the World Health Organization (WHO) classification, which takes into account cytogenetic and molecular genetic aberrations (5-7). These genetic alterations can serve as potent prognostic markers for AML (8). Additionally, epigenetic alterations have gained significance as contributors to AML pathogenesis (9). Consequently, AML is classified into favorable, intermediate and adverse risk groups based on newly recognized cytogenetic and molecular subsets, each displaying distinct responses to standard therapies (4). However, the translation of these novel biomarkers as tools for effective treatment decisions remains limited in clinical practice. Thus, the identification of molecular markers for risk-adapted therapies represents a critical goal in improving the clinical outcomes of AML (10).
Among the epigenetic mechanisms, genomic imprinting emerges as an interesting regulatory process that restricts gene expression to one of the two parental chromosomes. While the majority of the genes in the genome are expressed equally regardless of parental origin, a small subset of genes displays genomic imprinting (11). As of December 2018, ~165 imprinted genes in humans and 197 imprinted genes in mice have been reported (12). Although the exact mechanisms of imprinting remain elusive, the vital roles of imprinted genes in regulating cell proliferation and fetal growth are widely recognized (12,13). Consequently, dysregulated expression of imprinted genes has been implicated in tumorigenesis, exemplified by the upregulation of H19 imprinted maternally expressed transcript (H19) (10,14), insulin like growth factor 2 (IGF2) (14), maternally expressed 3 (MEG3) (15,16) and Zinc finger protein 215 (ZNF215) (14) genes in AML.
Significant progress has been achieved in the genomic profiling of AML, enabling the development of targeted therapies based on genomic characteristics. Nonetheless, the dysregulation of imprinted genes in AML remains relatively unexplored. A previous study conducted by the authors demonstrated that altered expression of imprinted genes and loss of ZNF215 imprinting can function as prognostic indicators for poor five-year survival in patients with cytogenetically abnormal (CA)-AML (14). Building upon these findings, the present study investigated whether the expression of imprinted genes is similarly altered in patients with cytogenetically normal (CN)-AML. The primary aim of the authors was to establish a possible correlation between this disease subtype and loss of imprinting.
Materials and methods
Patients and samples
Patients diagnosed with CN-AML were recruited from the Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital
(Kaohsiung, Taiwan) during the period spanning from August 1999 to October 2012. At the hospital, the standard protocol for diagnosis of AML included cytogenetic examination and mutational analysis. Immunophenotyping was conducted for the diagnosis of lymphocytic leukemia. The present study received ethical approval from the Institutional Review Board (IRB) of the Kaohsiung Medical University Hospital Ethical Committee (approval no. KMU-IRB-20130129; Kaohsiung, Taiwan). Written informed consent was provided by all participants.
BM samples were collected from 64 patients with CN-AML, while peripheral blood (PB) samples were obtained from 85 healthy adult volunteers. Within 1 h of collection, red blood cell (RBC) lysis buffer (MilliporeSigma) was added to the samples to deplete RBCs from both BM and PB samples. The isolated total leukocytes were then preserved in TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.) and stored in a -80˚C deep freezer until RNA extraction.
Cytogenetic analysis
Cytogenetic analysis was conducted on BM aspirate samples during the initial diagnosis using conventional G-banding cytogenetic techniques. Short-term unstimulated cell cultures were established for one to three days in RPMI-1640 medium supplemented with 20% fetal bovine serum (both from Invitrogen; Thermo Fisher Scientific, Inc.). A total of 20 metaphase cells with G-banded patterns were karyotyped and described according to the ISCN 2013 guidelines (17,18).
Selection of imprinted genes
Candidate imprinted genes were identified based on the Catalogue of Imprinted Genes- University of Otago from 2001(19), followed by a thorough evaluation using the Geneimprint Imprinted gene database (https://www.geneimprint.com/site/genes-by-species). Genes listed as either ‘predicted’ or ‘not imprinted’ were excluded from the study. Subsequently, a total of 16 human imprinted genes were selected, previously reported to be involved in various malignancies (14,20). Next, for primer design purposes, the sequences of these genes were acquired from the EnsEMBL human archive (Ensembl 54 NCBI 36; https://may2009.archive.ensembl.org/Homo_sapiens/Info/Index).
Expression analysis of imprinted genes
The expression analysis of imprinted genes adhered to the protocol is described in previous studies (14,20). Briefly, total RNA was isolated using TRIzol reagent (Invitrogen, Thermo Scientific, Inc.), followed by cDNA synthesis using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems; Thermo Scientific, Inc.) according to the manufacturer's protocols. Gene expression analysis was executed using SYBR® Green. Sequences of the forward and reverse primers of the 16 imprinted genes analyzed are listed in Table I. The primer sequences of reference gene ACTB (β-actin) were as follows: forward, 5'-GGCCAACCGCGAGAAGAT-3' and reverse, 5'-CGTCACCGGAGTCCATCAC-3'. In each reaction, 50 ng of cDNA, along with 200 nM of each primer, and 5 µl of 2x Power SYBR® Green PCR Master Mix (Applied Biosystems; Thermo Scientific, Inc.) were combined to a final volume of 10 µl. The PCR test was performed using a 7500 Fast Real-Time System (Applied Biosystems; Thermo Scientific, Inc.), employing the following thermal cycling parameters: An initial denaturation step at 95˚C for 10 min, followed by 40 cycles of PCR reaction at 95˚C for 20 sec and 60˚C for 60 sec. The expression of the ACTB gene in the same sample was used as an endogenous control. The ΔCq value for each imprinted gene was calculated using the equation ΔCq=(Cq of imprinted gene-Cq of ACTB gene) (21). Higher-ΔCq values indicate a higher expression level of the imprinted gene, while lower-ΔCq values indicate a lower expression level.
 | Table IList of imprinted genes and oligonucleotide primers for real-time quantitative polymerase chain reaction analysis. |
Statistical analysis
Statistical analyses were performed using SPSS 22.0 software (IBM Corp.) and GraphPad Prism 7.04 (Dotmatics). Results were presented as the mean ± SEM (standard error of mean). Variations in the expression of each imprinted gene between healthy subjects and CN-AML patients were assessed using the unpaired Student's t-test or Mann-Whitney test, depending on data distribution. Pearson correlation analysis was used to evaluate the correlation between two variables. To ascertain whether the expression of a specific imprinted gene could function as a predictor of survival in CN-AML, multivariate analysis using the Cox proportional hazards regression model was employed. The predictive capacity of the gene for the survival of the patients was evaluated by constructing a receiver operating characteristic (ROC) curve, with the calculation of the area under the curve (AUC). For comparison of patient survival across groups, Kaplan-Meier survival analysis and log-rank test were performed. Statistical analyses for expression analysis of imprinted genes were based on the -ΔCq values, with P<0.05 signifying statistical significance in all assessments.
Results
Patient characteristics
The present study included a total of 64 patients with CN-AML, consisting of 38 males and 26 females. Additionally, 85 healthy subjects, consisting of 47 males and 38 females, were enrolled in the present study. The age of the participants ranged from 23 to 57 years, with a median age of 36.3 years. Detailed information on the clinical characteristics of the patients, such as sex, age, laboratory data, and French-American-British (FAB) subtypes are presented in Table II. The diagnosis and subtyping of AML were determined based on the classification systems of FAB and WHO (15). To examine the karyotypes of patients at the time of initial diagnosis, conventional G-banding cytogenetic analysis was performed on BM aspirate samples.
| Table IICharacteristics of patients newly diagnosed with cytogenetically normal-acute myeloid leukemia (n=64). |
Expression of imprinted genes in patients with CN-AML
In a previous study conducted by the authors, altered expressions of imprinted genes in patients with CA-AML were observed (14). In the present study, the objective was to determine whether these genes were also altered in patients with CN-AML. For analysis, the same panel of 16 human imprinted genes was selected, namely C15orf2, COPG2, CPA4, GABRB3, H19, IGF2, INPP5F, L3MBTL, PEG3-AS, PPP1R9A, PRIM2, RTL1, SLC22A3, SNURF, TCEB3C and ZNF215. To initially screen the expression of these 16 genes, a cohort of 25 patients with AML, were randomly chosen regardless of their karyotypes, alongside 19 healthy subjects. The findings revealed that 8 of the genes exhibited upregulation in patients compared with the healthy subjects (Fig. 1). After the initial screening of 25 patients regardless of their karyotypes, the results were analyzed by segregating the cohort into CN-AML and CA-AML groups. The results from the broader 25-patient group aligned consistently with those exclusively from CN-AML patients. Therefore, the apprehension about discarding genes uniquely regulated in patients with CN-AML rather than patients with CA-AML during the initial screening was effectively addressed. Subsequently, for further validation, the focus shifted to a larger group comprising 64 patients with CN-AML and 85 healthy subjects. From the 8 genes previously identified (excluding C15orf2), the remaining 7 imprinted genes (COPG2, H19, IGF2, PEG3-AS1, PRIM2, SLC22A3 and ZNF215) that were upregulated in patients with CA-AML were similarly observed to be significantly upregulated in patients with CN-AML (P<0.001) when compared with healthy subjects (Fig. 2).
Correlation between expression of imprinted genes and clinical parameters of patients
To determine a possible association, Pearson correlation analysis was performed on the altered expression levels of seven imprinted genes in patients with CN-AML. The results, presented in Table III, revealed several significant correlations. Specifically, the expression levels of COPG2, PEG3AS, PRIM2 and ZNF215 were positively correlated with the percentage of blasts in PB (P<0.05). Finally, the expression level of H19 was positively correlated with the level of lactic dehydrogenase (P=0.040) in patients with CN-AML.
| Table IIICorrelation between expression of the 7 imprinted genes and clinical parameters in patients with cytogenetically normal-acute myeloid leukemia. |
Correlation, regression and survival analysis of expression of imprinted genes in patients with CN-AML
The correlation between the expression levels of the seven altered imprinted genes and the survival rate of patients with CN-AML was additionally explored. Pearson correlation analysis was conducted, revealing that among these seven genes, solely the expression level of H19 exhibited a negative correlation with the survival rate of the patients (P=0.018) (Table IV). Furthermore, the binary logistic analysis indicated that H19 could function as a predictive factor for the survival of patients with CN-AML [β=142.90, 95% Confidence interval (CI): 30.23-255.28, P=0.014].
| Table IVCorrelation between expression of the 7 imprinted genes and survival days in patients with cytogenetically normal-acute myeloid leukemia. |
To assess the impact of H19 on survival, a Cox proportional hazard model was utilized. The hazard ratio of H19 for two-year survival was computed as 0.852 (95.0% CI: 0.774-0.938, P=0.001), and for five-year survival, it stood at 0.882 (95.0% CI: 0.808-0.963, P=0.005).
Additionally, ROC analysis was performed to evaluate the area under the ROC curve (AUC) for two-year survival (AUC: 0.712, 95% CI: 0.582-0.843, P=0.006) (Fig. 3A). Using the cut-off point of H19 expression (-12.165), Kaplan-Meier survival analysis revealed that patients with lower H19 expression had a higher two-year survival rate (log-rank P=0.006; Fig. 3B) and improved five-year survival rate (log-rank P=0.029; Fig. 3C) compared with those with higher H19 expression.
Discussion
CN-AML constitutes a significant proportion (40-50%) of newly diagnosed AML cases and the identification of somatically acquired genetic alterations in both CA-AML and CN-AML groups is crucial for effective risk stratification. Despite presenting with a normal karyotype, patients with CN-AML exhibit various mutations, rendering them a heterogeneous group characterized by distinctive clinical outcomes (22). In the present study, by investigating the expression of imprinted genes, the authors aimed to identify possible prognostic biomarkers that could enhance treatment decisions for CN-AML.
Genomic imprinting plays a vital role in regulating growth and development, with its disruption frequently observed in the early stages of tumorigenesis (23,24). Consistent with the previous findings in CA-AML (14), significantly higher expression was observed in 7 out of the 16 imprinted genes analyzed in CN-AML. These results underscore the significance of imprinting and its dysregulation in AML, manifesting in cases with both normal and abnormal karyotypes.
The novel finding of the present study is the significant correlation between the H19 expression and the survival of patients with CN-AML. H19, the first reported human imprinted gene (25), has been demonstrated to promote leukemogenesis across diverse types of leukemia. In AML, increased H19 expression has been associated with poor prognosis (10,14,25,26) by inhibiting apoptosis through the targeting of miR-29a-3p (26) and miR-19a/b (27). Furthermore, loss of imprinting in the IGF2-H19 cluster has also been observed in a high percentage of patients with MDS and AML (28). Elevated H19 expression has been documented in acute lymphoblastic leukemia (29,30) and chronic myeloid leukemia (31,32), correlating with adverse outcomes in both cases. The oncogenic properties of H19, including inhibition of apoptosis, promotion of tumor cell proliferation, invasion, metastasis and chemoresistance, have been demonstrated across multiple solid tumors (33). Downstream targets of H19 in cancer include Akt2, β-catenin, FOXM1, RUNX1, STAT3 and miRNAs. Additionally, H19 can be transmitted to cancer cells via exosomes to promote tumor progression (34). Thus, H19 emerges as a potential biomarker and therapeutic target in both leukemia and solid tumors.
In addition to H19 and IGF2, the loss of imprinting of COPG2, PEG3-AS, PRIM2, SLC22A3 and ZNF215 genes in patients with CN-AML was observed. These genes have been associated with various malignancies and disorders, as discussed in the previous study conducted by the authors (14). The present study detected correlations between the expression of COPG2, H19, PEG3-AS, PRIM2, ZNF215 and clinical parameters in patients with CN-AML. However, only H19 expression was negatively correlated with patient survival. These results differ from the observations made in patients with CA-AML, further supporting the critical role of the loss of imprinting in the leukemogenesis of AML. The findings of the present study also indicated that specific imprinted genes are influenced under CA or CN conditions, leading to different clinical outcomes.
Over the past decade, numerous gene mutations in AML have been identified through genomics technologies (for example, RUNX1, IDH1, IDH2, DNMT3A, WT1, TET2, MLL, ASXL1, CBL, NRAS, KRAS and TP53 genes) (5,35). Patients with CN-AML, being the largest subgroup of AML, can be further classified into molecular subgroups based on these mutations. Targeted therapies are being developed to address these genetic and epigenetic changes, including demethylating agents and tyrosine kinase inhibitors (36). Although mutations in several genes (ACEBP, DNMT3A, FLT3-ITD, FLT3-TKD, IDH1, IDH2, MLL and NPM1) in the patients of the present study with CN-AML were analyzed, the presence or absence of these mutations did not significantly contribute to the prediction of patient survival (data not shown). Therefore, despite the inclusion of H19 as a prognostic marker, the application of novel biomarkers for treatment decisions remains limited. Future goals include improving the specificity of diagnostic classification to facilitate more efficacious targeted therapies and the development of personalized treatment strategies.
Similar to the previous study of the authors on CA-AML, the present study on CN-AML included certain limitations. Firstly, the samples obtained from healthy subjects were PB rather than BM. Secondly, the patient subgroups were relatively modest in size, posing constraints on more rigorous correlation analysis. Lastly, an inadequacy of post-treatment cases hindered the validation of the relationship between imprinted gene expression and disease status. Additionally, although novel and clinically relevant findings were observed, the functions of the altered imprinted genes in CN-AML were not examined. Studying H19 comes with its share of limitations and challenges. While it is established that H19 plays crucial roles in both normal development and disease, its functional complexity adds a layer of difficulty to comprehending its mechanisms. Moreover, the functions of H19 may vary among different cell types and tissues, highlighting the need to consider cell type specificity. Consequently, the effects observed in a specific context may not universally apply to all cell types or biological circumstances. H19 has been implicated in cancers. However, disease progression can involve numerous factors. Isolating the specific contribution of H19 among these factors can be intricate. Furthermore, it shows promise as a potential biomarker or therapeutic target in various diseases. Translating these findings into clinical applications can be a complex process involving validation, safety assessments and regulatory approvals.
Despite the extensive identification of cytogenetic and molecular biomarkers for AML, their application for diagnosis, prediction and treatment decisions remains limited. A recent study designed diagnostic models for diverse cancer types using measurements of elevated expression of imprinted genes (GNAS, GRB10 and SNRPN genes) (37). In combination with other molecular biomarkers such as gene mutations and expression of histone modifying genes, the integration of a panel of biomarkers could significantly enhance prediction sensitivity and specificity. In pursuit of this goal, forthcoming research should focus on elucidating the functions of altered imprinted genes in CA-AML and CN-AML, establishing histone modifications and exploring their clinical applications.
In conclusion, the present study revealed upregulated expression of 7 out of the 16 examined imprinted genes in BM samples from patients with CN-AML, indicating the involvement of loss of imprinting in the leukemogenesis of CN-AML. Notably, a significant negative correlation was observed between the H19 expression and the survival rate of CN-AML patients, highlighting its potential as a prognostic predictor for two- and five-year survival. The upregulated H19 expression observed in CN-AML implies its potential involvement in modulating cell proliferation, apoptosis and differentiation. Additionally, its interactions with other genes and regulatory factors may contribute to the intricate molecular pathways underlying CN-AML development and progression. By aligning the findings of the present study in CN-AML with the previous study on CA-AML, a substantiated connection between imprinted genes and AML has been established. Furthermore, the results suggest that expression of different imprinted genes are influenced by distinct cytogenetic conditions, leading to divergent clinical outcomes. To gain a deeper understanding of the roles these imprinted genes play in the leukemogenesis of both CA-AML and CN-AML, further functional studies are needed.
Acknowledgements
Not applicable.
Funding
Funding: The present study was supported by the Chang Gung Memorial Hospital (grant nos. CMRPG6J0251, CMRPD8E0171, CMRPD8J0011 and CMRPG6M0361). Further funding was provided by the National Science and Technology Council of Taiwan (grant nos. NSTC 103-2314-B-037-066-MY2 and NSTC 104-2314-B-037-035).
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
MYY conceptualized and supervised the study, acquired funding, wrote the original draft, wrote, reviewed and edited the manuscript. CMH conceptualized the study, acquired funding, wrote, reviewed and edited the manuscript. PML conducted investigation and developed methodology. CHY and MLH conducted investigation and project administration. IYC curated and validated data, performed formal analysis, and conducted software analysis. SFL conceptualized the study, acquired funding, wrote, reviewed and edited the manuscript. MYY and SFL confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
The present study was approved by the Institutional Review Board of the Kaohsiung Medical University Hospital Ethical Committee (approval no. KMU-IRB-20130129; Kaohsiung, Taiwan).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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