| کلیدواژههای انگلیسی مقاله |
SFRP2 protein, Humans, Leukemia, Myeloid, Acute, beta Catenin, Wnt signaling pathway, What&,rsquo s Known Wnt signaling is critical for the development of many malignancies, including acute myeloid leukemia. Research has shown the importance of the expression or methylation of secreted frizzled-related protein 2 as an antagonist and beta-cateninas a critical mediator of this pathway. What&,rsquo s New We investigated the status of both secreted frizzled-related protein 2expression and methylation simultaneously, and their correlation with beta-cateninexpression in Iranian patients. We showed that evaluating beta-cateninexpression might be valuable in predicting complete remission in patients with non-M3 acute myeloid leukemia. IntroductionAcute myeloid leukemia (AML) is a heterogeneous blood cancer characterized by the clonal disorders of hematopoietic progenitor cells. 1, , 2, Genetic and epigenetic abnormalities are considered to be a critical player in the pathogenesis of AML. 3, , 4, Aberrant promoter hypermethylation is one of many epigenetic aberrations that contribute to leukemogenesis. 5, In recent years, a considerable number of signaling pathways have been recognized and indicated as important factors for the regulation of cellular processes. The Wnt signaling pathway is one of them with a key role in hematopoietic cell fate. Based on numerous studies, the abnormal activation of the Wnt signaling pathway is indicated as the pathogenesis of AML, given its critical roles in differentiation, proliferation, cell adhesion, and migration. 6, , 7, Many instances of Wnt signaling dysregulation have been detected in various cancers, including AML. Wnt signaling comprises the canonical pathway (beta-catenin [&,beta -catenin]-dependent) and noncanonical pathways (&,beta -catenin-independent). 8, - 10, In the absence of Wnt signaling, the phosphorylated form of &,beta -catenin is degraded by ubiquitination, and the cytoplasmic levels of protein remain low. With the activation of the Wnt pathway, the phosphorylation and degradation of &,beta -catenin are inhibited, leading to its accumulation in the cytoplasm, and transport into the nucleus. Nuclear non-phosphorylated &,beta -catenin is the downstream effector of canonical Wnt signaling and mediates the expression of several genes, including cyclin D1 and c-Myc. 11, Several families of Wnt signaling antagonists such as secreted frizzled-related proteins (SFRP5), Dickkopf (Dkk) proteins, and Wnt inhibitory factor 1 act as modulators of the Wnt signaling cascade through the inhibition of Wnt proteins. 9, , 12, In humans, SFRP5 consist of five members, and have been implicated as the largest family among Wnt antagonists. The aberrant methylation of SFRP genes, which was associated with abnormal Wnt signaling activation, 13, , 14, was demonstrated in AML. 15, Four out of five SFRP genes (SFRP1, SFRP2, SFRP4, and SFRP5) contain dense CpG islands around their promoter regions. Previous studies have reported that SFRP genes, except for SFRP3 are silenced by promoter hypermethylation in various malignancies, including AML. 13, , 16, Moreover, it has been indicated that Wnt signaling can also be activated by mutant fms-like tyrosine kinase 3 (FLT3). 17, , 18, In total, these &,#64257 ndings show that Wnt signaling aberration involves multiple mechanisms, and is a common dysregulated pathway in various cancers. Furthermore, some studies have proposed that the hypermethylation of the SFRP promoter is an adverse risk factor for survival in patients with AML. 6, , 18, , 19, Accordingly, in the present study, we aimed to investigate the status of SFRP2 expression and methylation simultaneously and explore their clinical significance besides their correlation with the &,beta -catenin expression as the most important mediator of the canonical Wnt signaling pathway, in Iranian patients with de novo non-M3 AML. Patients and Methods Patients and SamplesIn this cross-sectional study, written informed consent was obtained before bone marrow specimens were collected from 188 patients with de novo non-M3 AML (98 male and 90 female patients), who were referred to the Hematology-Oncology and Stem Cell Transplantation Research Center of Shariati Hospital (Tehran, Iran) between January 2017 and February 2019. Based on previous studies and via the Cochran formula , the sample size was determined. 20, The diagnosis and classification of patients with de novo AML were made according to the criteria of the French-American-British (FAB) classification systems and the World Health Organization (WHO) (blast&,ge 20%). Patients, who had a history of other malignancies, myelodysplastic syndromes, and treatment with cytostatic drugs (e.g., steroids) were excluded from the study. The main clinical and laboratory features of the patients are summarized in table 1,. Sixty age- and sex-matched healthy controls with no current morbidity or history of serious diseases were included in the study. All the patients received standard 3+7 induction chemotherapy, comprising idarubicin (Pfizer, Australia 12 mg/m2) for three days plus cytarabine (Abbvie, Australia 100 mg/m2) for seven days. The project was approved by the Ethics Committee of Tehran University of Medical Sciences (code, IR.TUMS.REC.1395.2313).Patients&,rsquo Parameter(s)Status of SFRP2 ExpressionStatus of SFRP2 MethylationLow (n=136)High (n=52)Total (n=188)P valueM (120)U (68)P valueSex, Male 8216980.00662360.746Female 5436905832Median age, year (range)43 (14-90)54 (1-87)45 (1-90)0.00150 (1-90)42 (14-64)0.167Median WBC, &,times 109/L (range)25.41 (0.57-290.00)6.82 (0.98-62.81)20.62 (0.57-290.00)0.00314.31 (0.82-16.12)60.00 (0.57-290.00)0.083Median hemoglobin, g/L (range)79.00 (50.00-150.24)84.21 (40.20-120.16)80.11 (40.20-150.24)0.43682. 32 (40.20-150.24)76.20 (50.00-110.33)0.218Median platelets, &,times 109/L (range)17.00 (1.54-198.22)53.10 (13.08-369.18)40.12 (1.54-369.18)0.19134.51 (1.54-369.18)43.00 (1.89-198.71)0.175Age (year)&,lt 60116341500.00983670.675&,ge 60201838371BM blasts, % (range)86.51 (28.20-97.78)79.54 (30.1-97.78)82.00 (28.20-97.78)0.29582.00 (28.20-97.78)87.43 (30.10-97.78)0.307FAB type, n (%)M010 (7.3)0(0)10 (5.3)0.018 (6.7)2 (2.9)0.350M130 (22.1)12 (23.1)42 (22.3)26 (21.7)16 (23.5)M241 (30.1)12 (23.1)53 (28.2)34 (28.3)19 (28.0)M428 (20.6)25 (48.1)53 (28.2)33 (27.5)20 (29.4)M513 (9.6)1 (1.9)14 (7.4)10 (8.3)4 (5.9)M66 (4.4)2 (3.8)8 (4.3)4 (3.3)4 (5.9)Unclassified8 (5.9)0(0)8 (4.3)5 (4.2)3 (4.4)Gene mutation, n (%)NPM1 25(18.38)15 (28.84)40 (21.27)0.89130 (25.00)10 (14.7)0.283FLT3-ITD24 (17.64)16 (30.76)48 (25.53)0.44332 (26.67)16 (23.52)0.421Complete remission n(%)94 (69.12)38 (73.07)132 (70.21)0.10932 (26.67)23 (33.82)0.236Beta-catenin expression 0.238 0.843WBC, White blood cell BM, Bone marrow FAB, French&,ndash American&,ndash British SFRP2, Secreted frizzled-related protein 2 NPM1, Nucleophosmin 1 FLT3-ITD, FMS-like tyrosine kinase 3-internal tandem duplication |
| نویسندگان مقاله |
Fatemeh Mirzaeyan |
Department of Hematology and Blood Banking, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
Bahram Chahardouli |
Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Amin Mirzaeian |
Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
Nasrin Alizad Ghandforoush |
Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Kamran Alimoghaddam |
Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Shahrbano Rostami |
Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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