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Objective To analyze the prognostic impact of Ikaros family zinc finger 1(IKZF1)mutation on adult Philadelphia chromosome (Ph1) positive acute lymphoblastic leukemia (ALL) patients.Methods IKZF1 mutation was detected in 63 adult Phi positive ALL patients at diagnosis using capillary electrophoresis.Recruited patients were treated in our center and other three hospitals in Ningbo from January 2014 to January 2017.Clinical data were collected and retrospectively analyzed.Results Thirty-nine (61.9％) patients were positive IKZF1 mutation in this cohort.The white blood cell (WBC) count in IKZF1 mutation group was significantly higher than that of mutation negative group [(64.6±11.3)× 109/L vs.(33.7±5.6)×109/L,P＜0.05].Patients with WBC count over 30×109/L accounted for 56.4％ in IKZF1 mutation group.Complete remission (CR) rate in the IKZF1 mutation group was also lower than that of negative group after induction chemotherapy (64.1％ vs.75.0％,P＞0.05).IKZF1 was a negative prognostic factor but not independent factor for survival by univariate and multivariate analyses.Patients were divided into chemotherapy and allogeneic transplantation groups.The 3-year overall survival (OS) rate and 3-year leukemia-free survival (LFS) rate in IKZF1 mutation group were significantly lower than those of negative group in both transplantation group (42.3％ vs.59.3％;31.2％ vs.50.0％;respectively,both P＜0.05) and chemotherapy group (24.8％ vs.40.0％;19.0％ vs.34.3％;respectively,both P＜0.05).Conclusion IKZF1 mutation is a poor prognostic factor for adult Ph1 positive ALL patients.
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BACKGROUND: Ikaros family zinc finger 1 (IKZF1) is a transcription factor with an important role in controlling hematopoietic proliferation and function, particularly lymphoid cell differentiation. It was previously shown that various mechanisms and expression patterns of Ikaros are linked to a variety of cancers. We hypothesized that aberrant methylation (hypomethylation) of the IKZF1 promoter region might be one of the causes of B-cell acute lymphoblastic leukemia (B-ALL). In B-ALL patients, an increased expression of this gene is a potential cause of B-cell differentiation arrest and proliferation induction. Therefore, as more than 90% of patients with ALL are <15 years old, we investigated the methylation pattern of the IKZF1 promoter in childhood B-ALL. METHODS: Twenty-five newly diagnosed B-ALL cases were included (all younger than 15 yr). In addition, we selected 25 healthy age- and sex-matched children as the control group. We collected the blood samples in EDTA-containing tubes and isolated lymphocytes from whole blood using Ficoll 1.077 Lymphosep. Next, we extracted genomic DNA with the phenol/chloroform method. Two microgram of DNA per sample was treated with sodium bisulfite using the EpiTect Bisulfite Kit, followed by an assessment of DNA methylation by polymerase chain reaction (PCR) analysis of the bisulfite-modified genomic DNA. RESULTS: Our data highlighted a hypomethylated status of the IKZF1 promoter in the ALL cases (96% of the cases were unmethylated). In contrast, the control group samples were partially methylated (68%). CONCLUSION: This study demonstrated a hypomethylated pattern of the IKZF1 promoter region in childhood B-ALL, which might underlie the aberrant Ikaros expression patterns that were previously linked to this malignancy.
Subject(s)
Child , Humans , B-Lymphocytes , DNA , DNA Methylation , Ficoll , Hematologic Neoplasms , Leukemia , Lymphocytes , Methods , Methylation , Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Promoter Regions, Genetic , Sodium , Transcription Factors , Zinc FingersABSTRACT
Background@#Malignant pleural effusion (MPE) is a complicated condition of patients with advanced tumors. Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression.@*Methods@#The possible involvement of microRNAs (miRNAs) in malignant pleural fluid was investigated using small RNA sequencing. Regulatory T cell (Treg) markers (CD4, CD25, forkhead box P3), and Helios (also known as IKAROS Family Zinc Finger 2 [IKZF2]) were detected using flow cytometry. The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction. The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays. The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system. Correlation assays between miR-4772-3p and functional molecules of Tregs were performed.@*Results@#Compared with non-malignant controls, patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells. The verified downregulation of miR-4772-3p was inversely related to the Helios+ Tregs frequency and Helios expression in the MPE. Overexpression of miR-4772-3p could inhibit Helios expression in in vitro experiments. However, ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression. Additionally, miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA.@*Conclusion@#Downregulation of miR-4772-3p, by targeting Helios, contributes to enhanced Tregs activities in the MPE microenvironment.
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Ikaros represents a zinc-finger protein family important for lymphocyte development and certain other physiological processes. The number of family members is large, with alternative splicing producing various additional isoforms from each of the five homologous genes in the family. The functional forms of Ikaros proteins could be even more diverse due to protein-protein interactions readily established between family members. Emerging evidence suggests that targeting Ikaros proteins is feasible and effective in therapeutic applications, although the exact roles of Ikaros proteins remain elusive within the intricate regulatory networks in which they are involved. In this review we collect existing knowledge as to the functions, regulatory pathways, and molecular mechanisms of this family of proteins in an attempt to gain a better understanding through the comparison of activities and interactions among family members.
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Objective: To establish a molecular platform for screening thalidomide derivatives with potential high anti-tumor activities. Methods: Human cereblonvCRBN) and Ikaros family zinc finger protein l(IKZF1) cDNA were amplified and cloned into pXJ40-myc and pcDNA3-FLAG vectors respectively. Then the two constructs were transfected into 293T cells and the anti-tumor activities of thalidomide and its derivatives were reflected by their effects on the binding between CRBN and IKZF1 proteins. Results: Both CRBN and IKZF1 were successfully expressed in 293T cells. Thalidomide and two of its derivatives were found to enhance the interaction between CRBN and IKZF1 significantly. Conclusion: A molecular platform was successfully established for screening thalidomide derivatives with potential high anti-tumor activities and two thalidomide derivatives could potentiate the binding between CRBN and IKZF1. suggesting that they possess potential anti-tumor activities.
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Ikaros is a regulatory factor playing an important role in control of the development of hema-topoietic cells and immune system;and as a tumor suppressor,its aberration can cause both T and B lineage development arrest and neoplastic transformation,leading to insensitive to therapy and poor prognosis in actue lymphoblastic leukemia. Recently,researches on how Ikaros affects the leukemogenesis and prognosis become the focus of attention.
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objective To establish a molecular platform for screening thalidomide derivatives with potential high anti-tumor activities. Methods Human cereblon(CRBN) and Ikaros family zinc finger protein 1(IKZF1) cDNA were amplified and cloned into pXJ40-myc and pcDNA3-FLAG vectors respectively. Then the two constructs were transfected into 293T cells and the anti-tumor activities of thalidomide and its derivatives were reflected by their effects on the binding between CRBN and IKZF1 proteins. Results Both CRBN and IKZF1 were successfully expressed in 293T cells. Thalidomide and two of its derivatives were found to enhance the interaction between CRBN and IKZF1 significantly. Conclusion A molecular platform was successfully established for screening thalidomide derivatives with potential high anti-tumor activities and two thalidomide derivatives could potentiate the binding between CRBN and IKZF1, suggesting that they possess potential anti-tumor activities.
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Objective To investigate the expression and prognostic value of Ikaros6 in adult T-cell acute lymphoblastic leukemia(T-ALL) patients.Methods The RNA was extracted from mononuclear cells of bone marrow in 74 adult T-ALL patients.The expression of Ikaros6 was examined by reverse transcription-PCR,and the results were confirmed by sequencing.Clinical features and prognosis were analyzed based on clinical data.Results In 74 T-ALL patients,the incidence rate of Ikaros6 was 21.6 ％ (16/74).Extramedullary infiltrations were occurred often (x2 =4.084,P =0.043),had higher WBC (103.15 × 109/L vs 15.60×109/L,t =0.214,P =0.831),more severe anemia (75.95 g/L vs 107.00 g/L,t =1.504,P =0.142) and lower platelet count (26.0×109/L vs 67.0×109/L,t =1.421,P =0.164) in patients with Ikaros6 positive.Meanwhile Ikaros6-positive patients had inferior survival and were increased risk of relapse as compared with the Ikaros6-negative patients.Conclusions The incidence of Ikaros6 is high in adult T-ALL patients.Ikaros6-positive patients are more likely to have extramedullary infiltration and higher WBC,meanwhile they had inferior survival and increased risk of relapse.Thus Ikaros6 may be served as a valuable factor for risk stratification and prognosis evaluation in adult T-ALL patients.
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Objective To investigate the expression of Aiolos transcription factor in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE),and to explore their clinical significance.Methods Western blot was performed to detect the protein expression of Aiolos transcription factor in PBMCs from 19 patients with active SLE,13 patients with stable SLE and 30 healthy volunteers.The relationship between the expression of Aiolos transcription factor and SLE disease activity index (SLEDAI) was analyzed.Results A significant difference was noted in the relative expression of Aiolos transcription factor between SLE patients and normal controls(0.56±0.17 vs 0.81±0.09,P<0.01) and between patients in active stage and those in stable stage (0.52±0.14 vs 0.65±0.19,P<0.05).In addition,the expression level of Aiolos protein was negatively correlated with SLEDAI in patients (r=-0.65,P<0.01).Conclusion A decrease is observed in the expression of Aiolos transcription factor in SLE patients.which is correlated with the disease activity in SLE.
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Ikaros is a transcriptional factor playing an essential role in lymphoid lineage development and differentiation. Ikaros gene deletions occur in some acute lymphoblastic leukemia (ALL) patients, and the most common type of abnormality is overexpression of dominant negative isoforms 6 (Ik6). Deletion of Ikaros gene has an independent association with a very poor outcome in B-cell-progenitor ALL. A new subtype of ALL characterized by the deletion of Ikaros and poor outcome has been identified by researchers, and named BCR/ABL1 like ALL.We can conclude that Ikaros may play an important role in the diagnosis and treatment of pediatric ALL.