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Identification of LPCAT1 Expression As a Potential Prognostic Biomarker Guiding Treatment Choice in Acute Myeloid Leukemia

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Identification of LPCAT1 Expression As a Potential Prognostic Biomarker Guiding Treatment Choice in Acute Myeloid Leukemia ONCOLOGY LETTERS 21: 105, 2021 Identification ofLPCAT1 expression as a potential prognostic biomarker guiding treatment choice in acute myeloid leukemia KE WANG1, ZHIDAN WU1, YUAN SI1, WENDONG TANG1, XIN XU2, YAN CHENG1 and JIANG LIN1 Departments of 1Clinical Laboratory and 2Hematology, Jiangyin People's Hospital, Jiangyin, Jiangsu 214400, P.R. China Received July 11, 2020; Accepted November 3, 2020 DOI: 10.3892/ol.2020.12366 Abstract. Changes in lipid metabolism affect numerous among total cases of AML in the lower LPCAT1 expression cellular processes that are relevant to cancer biology, including group. These results suggest that patients with AML who cell proliferation, death, differentiation and motility. In the exhibit higher LPCAT1 expression levels may benefit from phosphatidylcholine biosynthesis pathway, the conversion HSCT. Collectively, the findings of the present study indicate of lysophosphatidylcholine (LPC) to phosphatidylcholine is that LPCAT1 expression may serve as an independent prog‑ catalyzed by cytosolic enzymes of the LPC acyltransferase nostic biomarker that can guide the choice between HSCT and (LPCAT) family. A number of studies have demonstrated chemotherapy in patients with AML. that LPCAT1 overexpression is a frequent event in diverse human cancer types, and that it is associated with unfavor‑ Introduction able pathological characteristics and patient survival. The aim of the present study was to explore the prognostic role Acute myeloid leukemia (AML) is an aggressive hemato‑ of the expression of LPCAT family members in acute logical malignancy with an incidence rate of 3.7 per 100,000 myeloid leukemia (AML). Using Cox regression analysis, worldwide, and it is characterized by the clonal proliferation of only LPCAT1 expression was identified as an independent myeloid hematopoietic stem cells with the inhibition of normal prognostic biomarker in AML. In a cohort from The Cancer hematopoiesis (1). AML is a highly heterogeneous disease Genome Atlas, Kaplan‑Meier analysis revealed that patients in terms of clinical presentation, cytogenetics/genetics and with AML and higher expression levels of LPCAT1 had clinical outcome (1). Due to its considerable variability, it is shorter overall survival (OS) and leukemia‑free survival recommended that AML treatment should be more personal‑ (LFS) times compared with those with lower expression levels ized and precisely targeted based on the risk classifications of of LPCAT1. This was further confirmed using an independent each patient (2). At present, the European LeukemiaNet risk cohort from the Gene Expression Omnibus. Using a third classification is widely used in the clinical management of cohort comprising patients with AML and healthy volunteers, AML; however, there is marked heterogeneity among patients it was confirmed that LPCAT1 expression was significantly in clinical practice, particularly those in intermediate groups in increased in newly diagnosed AML cases compared with the classification system (2). Therefore, it is crucial to identify healthy controls. Moreover, higher expression of LPCAT1 was novel potential prognostic and predictive biomarkers to improve associated with French‑American‑British subtype‑M4/M5 and our understanding of leukemogenesis so that molecular‑based nucleophosmin 1 mutations. Notably, patients who underwent stratification can be applied to risk‑adapted therapies and ulti‑ hematopoietic stem cell transplantation (HSCT) following mately improve the clinical outcome of AML. induction therapy exhibited significantly longer OS and LFS Changes in lipid metabolism affect numerous cellular times compared with patients who only received chemotherapy processes that are relevant to cancer biology, including cell after induction therapy in the higher LPCAT1 expression proliferation, death, differentiation and motility (3). In the group, whereas no significant differences in OS and LFS times phosphatidylcholine biosynthesis pathway, the conversion were observed between the HSCT and chemotherapy groups of lysophosphatidylcholine (LPC) to phosphatidylcholine is catalyzed by cytosolic enzymes of the LPC acyltransferase (LPCAT) family (4). To date, LPCAT1, LPCAT2, LPCAT3 and LPCAT4 have been identified and partially character‑ ized as the four members of the LPCAT family. A number of Correspondence to: Dr Jiang Lin, Department of Clinical Laboratory, Jiangyin People's Hospital, 163 Shoushan Road, studies have demonstrated that the overexpression of LPCAT1 Jiangyin, Jiangsu 214400, P.R. China is frequent in diverse human cancer types, including prostate E‑mail: [email protected] cancer (5,6), breast cancer (7,8), gastric cancer (9), clear cell renal cell carcinoma (10), lung cancer (11), hepatocel‑ Key words: LPCAT1, expression, prognosis, biomarker, acute lular carcinoma (12), oral squamous cell carcinoma (13) and myeloid leukemia colorectal cancer (14). Moreover, LPCAT1 overexpression has been found to be associated with unfavorable pathological characteristics and survival in several types of cancer (5‑11). 2 WANG et al: LPCAT FAMILY EXPRESSION IN AML However, the potential roles and clinical implications of LPCAT1 expression that occur during the development of LPCAT family members in AML remain poorly investigated. AML since PB contains blasts, and the collection of BM Therefore, the aim of the present study was to investigate the samples from patients with AML in the medical laboratory of prognostic role of the expression of LPCAT family members Jiangyin People's Hospital (Jiangyin, China) was challenging. in AML, and to determine whether this has the potential to be PB samples were collected from the 20 controls and the used as a new biomarker for the diagnosis and prognosis of 48 patients with AML at diagnosis, and from 15 of the patients AML, and for the optimization of clinical decision‑making in with AML at complete remission (CR). Nucleated cells were the treatment of the disease. obtained from PB using red blood cell lysis buffer (Beijing Solarbio Science & Technology Co., Ltd.). Total RNA was Materials and methods extracted from the PB nucleated cells using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.). Reverse transcrip‑ Patients. The first cohort included in the present study tion was performed to synthesize cDNA from the RNA using comprised 173 patients with AML for whom LPCAT family the PrimeScript™ RT reagent kit (Takara Bio, Inc.) according (LPCAT1/2/3/4) expression data were available from The to the manufacturer's instructions. Cancer Genome Atlas (TCGA) database (TCGA‑LAML, NEJM 2013) (https://cancergenome.nih.gov/ and http://www. Quantitative PCR (qPCR) analysis. qPCR analysis was cbioportal.org/) (15). The clinical and molecular characteris‑ conducted to detect LPCAT1 and GAPDH transcripts using tics obtained for the cohort included age (median, 58 years; TB Green Premix Ex Taq™ II (Takara Bio, Inc.). The primers age range, 18‑88 years), sex (81 male and 92 female), white used were as follows: LPCAT1 forward, 5'‑ACC TAT TCC blood cell (WBC) counts, peripheral blood (PB) blasts, bone GAGC CAT TGA CC‑3' and reverse, 5'‑CCT AAT CCA GCT marrow (BM) blasts, French‑American‑British (FAB) subtype, TCT TGC GAA C‑3'; and GAPDH forward, 5'‑AAT CCC ATC karyotype and the frequencies of known common genetic muta‑ ACC ATC TTC CAG‑3' and reverse, 5'‑GAG CCC CAG CCT tions, as well as gene expression levels. Due to the independent TCT CCA T‑3'. GAPDH served as the reference gene. qPCR disease entity of patients with FAB‑M3, the non‑M3 AML conditions were as follows: 95˚C for 30 sec, followed by cohort was used in the survival analysis. Following induction 40 cycles of 95˚C for 10 sec, 60˚C for 1 min, 72˚C for 1 min, chemotherapy, 100 of the patients received only chemotherapy and 80˚C for 30 sec. The relative LPCAT1 transcript level was as a consolidation treatment, whereas 73 patients underwent calculated using on the 2‑∆∆Cq method (20). hematopoietic stem cell transplantation (HSCT) with/without chemotherapy as a consolidation treatment. This cohort of Statistical analysis. The Mann‑Whitney U test or the patients with AML was used for the identification of LPCAT Kruskal‑Wallis test followed by Dunn's post hoc test was used family members whose expression was associated with for the comparison of continuous variables, and Pearson's χ2 or prognosis, and for the analysis of the clinical implications of Fisher's exact test were used for the comparison of categorical LPCAT1 expression. variables. The effect of LPCAT1 expression on leukemia‑free A second cohort was also included, comprising 78 survival (LFS) and overall survival (OS) was analyzed using patients (median age, 62 years, age range 18‑85 years) with the Kaplan‑Meier method with log‑rank test, and Cox regression cytogenetically normal AML (CN‑AML) from a Gene analysis. Two‑tailed P‑values of <0.05 in all statistical analyses Expression Omnibus (GEO) dataset (GSE12417) (16). The were considered to indicate a statistically significant difference. online tool GenomicScape (http://genomicscape.com/micro‑ array/survival.php) was applied to validate the prognostic value Results of LPCAT1 expression among the patients with CN‑AML in this cohort (17). Identification of prognosis‑associated LPCAT family member A third cohort, comprising 48 patients with AML (26 male expression in AML. To investigate the prognostic value of and 22 female; median age, 60 years; age range, 18‑82 years) LPCAT family members in AML, expression data on all LPCAT and 20 healthy volunteers
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