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Association Between the CEBPA and C-MYC Genes Expression Levels and Acute Myeloid Leukemia Pathogenesis and Development

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Association Between the CEBPA and C-MYC Genes Expression Levels and Acute Myeloid Leukemia Pathogenesis and Development Medical Oncology (2020) 37:109 https://doi.org/10.1007/s12032-020-01436-z ORIGINAL PAPER Association between the CEBPA and c-MYC genes expression levels and acute myeloid leukemia pathogenesis and development Adrian Krygier1 · Dagmara Szmajda‑Krygier1 · Aleksandra Sałagacka‑Kubiak1 · Krzysztof Jamroziak2 · Marta Żebrowska‑Nawrocka1 · Ewa Balcerczak1 Received: 27 September 2020 / Accepted: 27 October 2020 / Published online: 10 November 2020 © The Author(s) 2020 Abstract CEBPA and c-MYC genes belong to TF and play an essential role in hematologic malignancies development. Furthermore, these genes also co-regulate with RUNX1 and lead to bone marrow diferentiation and may contribute to the leukemic trans- formation. Understanding the function and full characteristics of selected genes in the group of patients with AML can be helpful in assessing prognosis, and their usefulness as prognostic factors can be revealed. The aim of the study was to evaluate CEBPA and c-MYC mRNA expression level and to seek their association with demographical and clinical features of AML patients such as: age, gender, FAB classifcation, mortality or leukemia cell karyotype. Obtained results were also correlated with the expression level of the RUNX gene family. To assess of relative gene expression level the qPCR method was used. The expression levels of CEBPA and c-MYC gene varied among patients. Neither CEBPA nor c-MYC expression levels dif- fered signifcantly between women and men (p=0.8325 and p=0.1698, respectively). No statistically signifcant correlation between age at the time of diagnosis and expression of CEBPA (p=0.4314) or c-MYC (p=0.9524) was stated. There were no signifcant associations between relative CEBPA (p=0.4247) or c-MYC (p=0.4655) expression level and FAB subtype and mortality among the enrolled patients (p=0.5858 and p=0.8437, respectively). However, it was observed that c-MYC and RUNX1 expression levels were signifcantly positively correlated (rS=0.328, p=0.0411). Overall, AML pathogenesis involves a complex interaction among CEBPA, c-MYC and RUNX family genes. Keywords CEBPA gene · c-MYC gene · Transcription factors · Gene expression level · qPCR · AML · Adult leukemia * Adrian Krygier Introduction [email protected] Dagmara Szmajda-Krygier Acute myeloid leukemia (AML) belongs to the group of [email protected] heterogeneous neoplastic diseases of the white blood cell Aleksandra Sałagacka-Kubiak system. AML is characterized by clonal proliferation and [email protected] growth of cancer-transformed blast cells that originate from Krzysztof Jamroziak the precursor myeloid cell in the bone marrow and in the [email protected] peripheral blood [1, 2]. AML accounts for ~80% of all acute Marta Żebrowska-Nawrocka leukemias in adults and this number has been revealed to [email protected] increase with age. AML most commonly occurs in older Ewa Balcerczak adults and is cured in approximately 35–40% of patients [email protected] younger than the age of 60, however, in the group of patients >60 years, cases of full recovery are less common [1–4]. 1 Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical The course of acute myeloid leukemia is extremely severe: Biochemistry and Molecular Diagnostics, Medical if left untreated, it can lead to the death of a patient within a University of Lodz, Muszynskiego 1 Street, 90-151 Lodz, few weeks. The pathogenesis of this disease is still not fully Poland understood. Among genetic factors which can lead to AML 2 Department of Hematology, Institute of Hematology development, chromosome aberrations (which are observed and Transfusion Medicine, Chocimska 5 Street, in 50–60% of AML patients) such as translocations: t(8; 21) 00-791 Warsaw, Poland Vol.:(0123456789)1 3 109 Page 2 of 10 Medical Oncology (2020) 37:109 (q22; q22) or (15; 17) (q22; q21), deletions: del (5q) or del that the expression of proto-oncogene MYC is also tightly (7q) and chromosomal inversions: inv (3), inv (8), or inv regulated during hematopoiesis [24]. Various studies sug- (16) can be distinguished [5]. The presence of mutations in gest that c-MYC gene is dysregulated in cancers, including the genes which are mainly responsible for proliferation and leukemias. The expression of c-MYC is highest in hemat- increasing the survival of progenitor cells, such as: FLT3, opoietic stem cells (HSCs) and decreases during myeloid RAS, KIT or TP53, may also predispose to AML develop- diferentiation [11]. There is also an association between ment [4]. Growing evidence point to the role of molecular the activity of c-MYC and CEBPA genes. Downregula- indicators of tumor transformation, which may contribute tion of MYC expression causes repression on key target to the formation of a self-regenerating leukemia cell clone. genes, such as CEBPA or GADD45A and, in consequence, Among genetic aberrations potentially related to the devel- it initiates hematopoietic diferentiation and apoptosis, opment of AML or prognosis assessment among patients, respectively [25]. changes in genes coding for the so-called transcription fac- Understanding the function and full characteristics of tors (including RUNX1, RUNX3, CEBPA, ASXL1) regu- CEBPA and c-MYC genes in the group of patients with acute lating transcription processes as well as controlling the cell myeloid leukemia can be particularly helpful in assessing diferentiation and formation seem signifcant [4, 6]. prognosis, and their usefulness as prognostic factors can Numerous studies support the complementary role of be revealed. This may translate into the development of CEBPA and c-MYC transcription factors in risk stratifcation new targeted therapeutic strategies and an increase in the of hematologic malignancies development [7–12]. Addition- efectiveness of treatment in patients with acute myeloid ally, according to the available data, the RUNX1 gene infu- leukemia. ences and regulates the CEBPA and c-MYC gene expression The aim of the study was to evaluate CEBPA and c-MYC [13, 14]. It has been proven that the deletion of the RUNX1 mRNA expression level and their association with clinical gene reduces the mRNA level of the CEBPA gene. This leads and pathological features of AML patients. Moreover, the to impaired bone marrow diferentiation and may contribute obtained results of selected genes expression levels were to the leukemic transformation in cases of acute myeloid leu- correlated with the expression level of genes belonging to kemia associated with the decreased RUNX1 activity [14]. the RUNX family (including RUNX1 and RUNX3) evaluated On the other hand, properly functioning RUNX1 protein for the same study group (published data). binds at three c-MYC distal enhancers where it represses c-MYC expression leading to apoptosis of AML cells [15]. CCAAT Enhancer Binding Protein Alpha (CEBPA) is an intronless gene located on chromosome 19q13.1. CEBPA Materials and methods gene encodes protein belonging to transcription factors fam- ily containing a basic leucine zipper (bZIP) domain which Study group recognizes the CCAAT motif in the promoter regions of target genes [16]. C/EBPα protein regulates the expression The study population comprised 46 patients (22 females of genes involved in cell cycle processes or homeostasis of and 24 males). All recruited patients were diagnosed with body weight [16, 17]. Furthermore, C/EBPα is a critical reg- AML at the Hematology Clinic, the Medical University of ulator of granulopoiesis and its expression enables hemat- Lodz (Lodz, Poland) and the Institute of Hematology and opoietic progenitors to diferentiate [18]. Growing evidence Blood Transfusion (Warsaw, Poland). The median age at the indicate that CEBPA gene probably acts as a tumor suppres- time of AML diagnosis was 61.5 years (17–80 years). The sor in hematologic and non-hematologic malignancies [19]. Ethics Committee of Medical University of Lodz approved Moreover, mutations of this gene are associated with acute the present study (protocol number RNN/88/16/KE) and it myeloid leukemia. was in accordance with the principles of the Declaration of Another gene belonging to the transcription factors Helsinki. Written informed consent was obtained from the is BHLH Transcription Factor c-MYC gene. c-MYC is a all recruited patients. All data collected in the study were proto-oncogene which is located on chromosome 8 q24.21. anonymous. All demographic and clinical characteristics of It encodes a nuclear phosphoprotein that plays an essential patients are presented in Table 1. role in cell cycle progression, cellular transformation and apoptosis [20, 21]. Furthermore, encoded protein forms a complex with the related transcription factor MAX, Material which binds with the E box DNA consensus sequence and regulates specifc target gene transcription. c-MYC is The investigated material comprised peripheral blood sam- associated with Burkitt Lymphoma or High-Grade B-Cell ples which were obtained during routine blood tests. Lymphoma development [22, 23]. Recent studies indicate 1 3 Medical Oncology (2020) 37:109 Page 3 of 10 109 Table 1 Demographic and clinical characteristics of patients mM MgCl2, 0.4 μl of 0.2 mM dNTP (deoxynucleotides) mix, Characteristics Number 0.2 μl of 0.5 U AccuTaq LA DNA Polymerase, 1 μl of cDNA of patients and 13.8 μl distilled water. The fnal volume of reaction mix- (n=46) ture was 21 μl. For each experiment a negative control with- out cDNA template was included. The PCR amplifcations Gender for investigated and reference genes were carried out using Men 24 an MJ Mini Personal Thermal Cycler (BioRad Laboratories, Women 22 Inc., Hercules, CA, USA). Thermal conditions were as fol- Age at the time of AML diagnosis (years) lows: initial denaturation at 95°C for 2 min, denaturation at Range (mean) 17-80 (61.5) 95°C for 1 min, annealing at 56°C for CEBPA and 57°C for Leukemia subtype according to FAB classifcation (%) MYC for 30 sec, elongation at 72°C for 45 sec and fnal elon- M0 2.2 (n=1) gation at 72°C for 5 min.
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