IKZF1 gene located in 7p12 of chromosome, and Ikaros family zinc finger encoded by IKZF1, are lymphoid-restricted transcription factors. In recent years, it has been demonstrated that the mutation of IKZF1 gene involved in proliferation, metastasis and prognosis of many malignant tumor except acute lymphoblastic leukemia, and also involved in complex phenotypes and susceptibility to systemic lupus erythematosus. This review briefly introduces the molecular structure and physiological function of Ikaros, focusing on its function and molecular mechanism in proliferation, metastasis and prognosis of malignant tumors, and its role in the systemic lupus erythematosus.
Humans ; Ikaros Transcription Factor ; Lupus Erythematosus, Systemic ; Neoplasms ; Prognosis

The Ikaros - a DNA-binding zinc finger protein, acting as a regulator of chromatin remodeling and gene transcription, is crucial for regulating the development and function of the immune system and acting as a master regulator of hematopoietic differentiation. Function-loss mutations of IKZF1, gene encoding Ikaros are frequent in B cell acute lymphoblastic leukemia (B-ALL) and are associated with a poor prognosis. This review briefly summarizes the available data regarding the structure and function of Ikaros, the role of Ikaros as a tumor suppressor in B-ALL, and its regulation mechanism.
B-Lymphocytes ; Cell Differentiation ; Genes, Tumor Suppressor ; Humans ; Ikaros Transcription Factor ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma

OBJECTIVE: To study the clinical features of acute lymphoblastic leukemia (ALL) in children with IKAROS family zinc finger 1 (IKZF1) deletion, and to observe the effect of increasing the intensity of chemotherapy on the prognosis of this disease. METHODS: A total of 278 children diagnosed with ALL between December 2015 and February 2018 were systematically treated according to the Chinese Children's Leukemia Group-ALL 2008 protocol (CCLG-ALL 2008). The patients were divided into an IKZF1-deleted group and a control group according to the presence or absence of IKZF1. The IKZF1-deleted group was treated with the regimen for high-risk group (HR) in the CCLG-ALL 2008 protocol, while the control group received different intensities of chemotherapy according to clinical risk classification. The clinical features and event-free survival rate (EFS) were compared between the two groups. RESULTS: A total of 24 (8.6%) cases of 278 children were found to have large deletions of exons of the IKZF1 gene. The IKZF1-deleted group had significantly higher proportions of cases with white blood cell count ≥50×10/L at initial diagnosis, BCR-ABL1 fusion gene positive, minimal residual disease ≥10% on the 15th day of induction remission treatment, minimal residual disease-high risk and clinical risk classification-high risk compared with the control group (P<0.05). The 3-year EFS rate (76%±10%) in the IKZF1-deleted group was lower than that in the control group (84%±4%), but with no significant difference between the two groups (P=0.282). The estimated 3-year EFS rate in the IKZF1-deleted-non-HR group (actually treated with the chemotherapy regimen for HR in the CCLG-ALL 2008 protocol) was 82%±12%, which was lower than that in the control-non-HR group (86%±5%), but there was no significant difference (P=0.436). CONCLUSIONS ALL children with IKZF1 deletion have worse early treatment response, and increasing the intensity of chemotherapy might improve the prognosis.
Disease-Free Survival ; Gene Deletion ; Humans ; Ikaros Transcription Factor ; genetics ; Neoplasm, Residual ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis

Objective: This study aimed to investigate the prognostic significance of IKZF1 gene deletion in patients with acute B lymphoblastic leukemia (B-ALL) . Methods: The clinical data of 142 patients with B-ALL diagnosed in Nanfang Hospital between March 2016 and September 2019 were analyzed. Results: IKZF1 deletion was found in 36.0% of the 142 patients with B-ALL, whereas exon 4-7 deletion was found in 44.0% . White blood cell counts were higher in patients with the IKZF1 deletion (52.0% and 28.3% , P=0.005) ; these patients also experienced worse effects of mid-term induction therapy (40.0% and 70.7% , P<0.001) and had a higher proportion of Philadelphia chromosome-positive (52.0% and 21.7% , respectively, P<0.001) . Univariate analysis revealed that the 3-year overall survival rate (OS) and event-free survival rate (EFS) in the IKZF1 deletion group were significantly lower than the IKZF1 wild-type group [ (37.1±7.3) % vs (54.7±5.4) % , (51.8±7.9) % vs (73.9±4.7) % ; P=0.025, 0.013, respectively]. Multivariable analysis showed that harboring IKZF1 deletion was an adverse factor of EFS and OS (HR=1.744, 2.036; P=0.022, 0.020, respectively) . Furthermore, the IKZF1 deletion/chemotherapy group had significantly lower 3-year OS, EFS, and disease-free survival rates than other subgroups. In the IKZF1 deletion cohort, allo-hematopoietic stem cell transplantation (HSCT) significantly improved OS and EFS compared to non-allo-HSCT[ (67.9±10.4) % vs (31.9±11.0) % , (46.6±10.5) % vs (26.7±9.7) % ; P=0.005, 0.026, respectively]. Conclusion: Pediatric-inspired chemotherapy was unable to completely reverse the negative effect of IKZF1 deletion on prognosis. Pediatric-inspired regimen therapy combined with allo-HSCT, in contrast, significantly improved the overall prognosis of IKZF1 deletion B-ALL.
Acute Disease ; Burkitt Lymphoma ; Child ; Gene Deletion ; Humans ; Ikaros Transcription Factor/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Prognosis

OBJECTIVETo analyze the isoforms of IKAROS in the bone marrow samples from children with acute B-lineage lymphoblastic leukemia (B-ALL) and to investigate the relationship between frequency of dominant-negative (DN) IKAROS isoforms and prognosis of B-ALL, and to preliminarily study the relevant mechanism.

METHODSA total of 137 children with newly diagnosed B-ALL, who sequentially entered the Department of Hematology and Oncology, Shanghai Children's Medical Center between January 2005 and September 2010, were included in the study. Nest-PCR, Sanger sequencing, and TA cloning were used to analyze the expression of IKAROS isoforms in these children. The relationship between frequency of DN IKAROS isoforms and prognosis of B-ALL was investigated.

RESULTSOf the 137 children with newly diagnosed B-ALL, 16 had expression of IK6, 14 had expression of IK4, and 2 had expression of IK7. There was significant difference in 2.5-year event-free survival between the cohorts of DN IKAROS and non-DN IKAROS (P=0.01). Analysis of the 10 paired of diagnosis/relapse samples from 10 patients with recurrence showed that 8 of 10 paired diagnosis and relapse samples had inconsistent expression of IKAROS isoforms. The rate of IK6 expression in relapse samples from 21 relapse ALL patients was significantly higher than in the 137 children with newly diagnosed ALL (62% vs 12%, P<0.01).

CONCLUSIONSExpression of DN IKAROS isoforms can be a poor prognostic factor in B-ALL and is closely associated with recurrence of B-ALL.

Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Ikaros Transcription Factor ; genetics ; Infant ; Male ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; metabolism ; mortality ; Prognosis ; Protein Isoforms ; genetics

This study was aimed to detect the expression of IKZF1 gene isoforms in bone marrow cells of patients with adult acute lymphoblastic leukemia and to investigate the clinical characteristics and prognosis of patients with IK6 isoform. The expression of IKZF1 gene isoforms were measured by nested RT-PCR in 79 newly diagnosed ALL patients. The clinical characteristics of IK6 positive patients and overall survival, disease-free survival of the IK6 positive group and IK6 negative group were compared. The results showed that IK1 and IK2/3 were the functional isoform while the IK4, IK6, IK8 and IK9 were the dominant negative isoform in adult ALL. The dominant negative isoform IK6 accounted for 34.4% in B-ALL patients and accounted for 22.2% in T-ALL patients. The BCR/ABL1 positive rate and the percentage of high risk patients in IK6 positive group was higher than that of IK6 negtive group in B-ALL patients (P = 0.027, P = 0.048). The expression of IK6 isoform did not correlate with sex, age and WBC count of B-ALL and T-ALL patients. The overall survival and disease-free survival of IK6 positive group were both lower than that of IK6 negtive group in Ph negative B-ALL patients (P = 0.009, P = 0.002). It is concluded that IK6 is a main isoform of the expression of IKZF1 gene in adult ALL patients, and can be used as a prognostic factor for guiding treatment in Ph negative B-ALL patients.
Adolescent ; Adult ; Aged ; Female ; Humans ; Ikaros Transcription Factor ; genetics ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; genetics ; Prognosis ; Protein Isoforms ; genetics ; Young Adult

OBJECTIVETo identify ikaros family zinc finger1 (IKZF1) deletion in patients with pediatric B cells-acute lymphoblastic leukemia (B-ALL) without reproducible chromosomal abnomalities and further investigate its value in this part of patients' pathogenesis and prognosis.

METHODThe study was approved by the institutional review board of the authors' hospital and informed consent was obtained from the patients and/or their legal guardians. Data of 96 children with B-ALL patients without reproducible cytogenetic abnormalities whose bone marrows specimens were enough for DNA extraction for the detection were retrospectively selected. All the patients were diagnosed and systematically treated according to CCLG-ALL2008 in our hospital from April 2008 to April 2013. The 96 patients were divided into two groups according to the result of IKZF1's detection by multiplex ligation-dependent probe amplification (MLPA): The cases that with any of eight exons of IKZF1 deleted were entered into"Group with IKZF1 deletion"otherwise entered"Group without IKZF1 deletion". Disease free survival (DFS), event-free survival (EFS) and overall survival (OS) were compared between the two groups.

RESULTNineteen out of 96 B-ALL patients without reproducible cytogenetic abnormalities had IKZF1 deletion (20%). Three of 19 patients with IKZF1 deletions of the whole gene; ten of 19 patients with IKZF1 deletions of exon 1; 4 of 19 patients with IKZF1 deletions of exons 4-7; one of 19 patients with IKZF1 deletions of exons 2-7 and one of 19 patients with IKZF1 deletions of exons 1-6. Whose white blood cell (WBC) ≥ 50 × 10(9)/L inIKZF1 diletion group was more than whthout IKZF1 deletion group(42% vs. 13%, P=0.004). Patients with IKZF1 deletions had a lower 3-year DFS (0.67 ± 0.13 vs. 0.93 ± 0.04, P=0.001); EFS (0.67 ± 0.13 vs. 0.90 ± 0.04, P = 0.012) and OS(0.79 ± 0.09 vs. 0.96 ± 0.02, P=0.010) compared to those without IKZF1 deletions. Excluding the influence of sex, age, WBC count at diagnosis, cerebrospinal fluid state and prednisone response IKZF1 deletion still affected the patients' DFS, EFS and OS ( P<0.05 for all comparisons).

CONCLUSIONSome of pediatric B-cell precursor ALL without reproducible cytogenetic abnormalities had been detected to have IKZF1 deletion; IKZF1 deletion is an independent poor prognostic factor in these patients.

Child ; Chromosome Aberrations ; Disease-Free Survival ; Exons ; Gene Deletion ; Humans ; Ikaros Transcription Factor ; genetics ; Multiplex Polymerase Chain Reaction ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Prognosis ; Zinc Fingers

This study was aimed to evaluate IKAROS6 expression in patients with chronic myelogenous leukemia (CML) and its clinical significance. cDNAs from 73 CML patients were amplified by PCR and sequenced for IKAROS expression to elucidate clinical characteristics in IKAROS6 positive patients. The results showed that there was no IKAROS6 gene expression in 8 healthy controls and 15 CML patients in chronic phase and accelerated phase, and 15 cases (35.71%) were IKAROS6 positive in lymphoblast crisis samples among 42 newly diagnosed CML; however, none was found in myeloblast crisis of 16 newly diagnosed CML. Among 42 lymphoblast crisis of CML, the complete remission (CR) rate of IKAROS6 expression positive patients reached 40% (6/15), which was obviously lower than that in IKAROS6 negative patients (85.19%, 23/27) (p < 0.01), IKAROS6 positive patients relapsed after CR for 15 (2 - 18) months with relapse rate 66.7% (4/6), which was higher than that in expressed wild type IKAROS gene patients (21.74%, 5/23) (p < 0.05). It is concluded that abnormal expression of IKAROS gene dominated by IKAROS6 isoforms can be detected in lymphoblast crisis samples of CML patients. Abnormal expression of IKAROS gene may be an important factor in lymphoblast crisis of CML. Therefore, detection of IKAROS gene expression may be important for target therapy and evaluation of clinical prognosis of CML patients.
Adolescent ; Adult ; Aged ; Child ; Female ; Gene Expression ; Humans ; Ikaros Transcription Factor ; genetics ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Male ; Middle Aged ; Prognosis ; Young Adult

The purpose of this study was to construct a lentiviral vector carrying IK6 gene and to observe the expression of IK6 as well as related biologic feature in THP1 cells, so as to provide an effective method to further investigate the role of this gene in leukemia. The IK6 gene was obtained by using reverse transcription polymerase chain reaction (RT-PCR). Then IK6 was recombined with the pGC-FU vector to construct a recombinant lentiviral vector named pGC-FU-IK6 gene-GFP,which was confirmed by PCR and sequencing. The 293T cells were transfected with pGC-FU- IK6-GFP by using Lipofectamine 2000. After examining the titer of the virus, pGC-FU- IK6-GFP was used to transfect THP1 cells. The transfection efficiency was detected by flow cytometry, and the expression level of mRNA and IK6-GFP fusion protein were confirmed by RT-PCR and Western blot respectively. Then the impact of IK6 on apoptosis and cell cycle was analyzed. The results showed that the IK6 gene was obtained by RT-PCR and connected into the linearized lentiviral vector to successfully constructed target plasmid named pGC-FU-IK6-GFP with Amp resistant. The target plasmid was transfected into 293T cells and the virus titer was 2.0×10(9)TU/ml. Next, THP1 cells were transfected with pGC-FU-IK6-GFP and the efficiency was up to 90%. The detection of the IK6 mRNA and IK6-GFP fusion protein in target cells showed that IK6 could promote target cell clone formation and inhibit apoptosis, but had no significant effect on the cell cycle. It is concluded that virus vector carrying IK6 gene had been successfully constructed and expressed in THP1 stably. Biology studies of target THP1 cell shows that the IK6 is likely to interfere with the function of normal Ikaros protein as tumor suppressor, and it exerts a potential anti-apoptotic effect. Thus, IK6 can promote leukemia cell growth. However, there is no significant effect on the cell cycle. It provides an effective method for exploring the function of IK6 in acute myeloid leukemia.
Apoptosis ; Cell Cycle ; Cell Line, Tumor ; Gene Expression ; Genetic Vectors ; Humans ; Ikaros Transcription Factor ; genetics ; metabolism ; Lentivirus ; genetics ; Leukemia, Monocytic, Acute ; metabolism ; Plasmids ; Transfection

OBJECTIVE: To explore the possible molecular mechanism of Ikaros regulation on FUT4 expression by analyzing the correlation of the functional state of Ikaros with level of FUT4 expression, so as to provide the theoretical basis for personalized treatment in children with ALL. METHODS: The subtypes of Ikaros were identified by nested PCR and sequencing. The expression level of FUT4 was detected by quantitative PCR and analyzed by ΔΔCt method in the early stage of treatment, remission and relapse of ALL. RESULTS: Ik1 and Ik2 were the main functional subtypes, and the dominant negative Ikaros was Ik6; the Ik6 was detected in 23 patients with ALL. It was found that 2.73% patients expressing Ik6 alone and 18.18% patients with heterozygous expression were detected. The expression of FUT4 in the newly diagnosed ALL was higher than that in the control group, and the functional Ikaros negatively correlated with the FUT4 expression(r=-0.6329). CONCLUSION Dominant negative Ikaros closely correlated with the relapse of acute lymphoblastic leukemia in children. The functional Ikaros negatively correlated with FUT4 expression. Ikaros inhibit the transcriptional activity of FUT4, that may be the molecular mechanism of Ikaros regulating the expression of FUT4.
Acute Disease ; Child ; Fucosyltransferases ; metabolism ; Humans ; Ikaros Transcription Factor ; metabolism ; Lewis X Antigen ; metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Protein Isoforms ; Recurrence