Expression Characteristics And Prognosis Of IKZF1 Gene Deletion In Children With Acute B-lymphoblastic Leukemia

BackgroundAcute lymphoblastic leukemia(ALL)is a disease caused by abnormal hyperplasia of lymphoid precursor cells.It is the most common childhood malignant clonal tumor,among which acute B-lymphoblastic leukemia(B-ALL)is the most common type of ALL in children.In recent years,with the understanding of the pathogenic mechanism,diagnosis and treatment of children's ALL,its long-term disease-free survival rate has significantly improved.However,some children have not reached remission or relapsed during the treatment process.Research the factors associated with poor prognosis in children with ALL are essential.IKZF1 gene is one of the important regulatory genes of the hematopoietic system.It encodes the transcription factor IKAROS,which has the function of regulating lymphocyte production,and plays an important role in different stages of differentiation such as normal bone marrow,lymphocytes,red blood cells and megakaryocytes.In children with ALL,those who have IKZF1 gene deletion always have a poor prognosis,but at present,the opinions on whether IKZF1 gene deletion can be used as an independent risk factor for poor prognosis in children with B-ALL are not completely unified and more research is needed.Objective:By analyzing the clinical data of IKZF1 gene deletion group and non-deletion group in 367 children with B-ALL,the expression characteristics and prognostic impact of IKZF1 gene deletion in children with B-ALL were explored.Methods:The clinical data of 367 children with B-ALL diagnosed for the first time in the Department of Hematology and Oncology of the First Affiliated Hospital of Zhengzhou University from January 1,2014 to December 31,2016 were collected.After obtaining the parent's informed consent,3-5 ml of bone marrow fluid of every child was collected before starting chemotherapy,and then the real-time quantitative PCR technology was used to detect the loss of IKZF1 gene.This study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.?Divide the 367 children with B-ALL into the IKZF1 gene deletion group and non-deletion group,then analyze the clinical characteristics,laboratory test indicators,and prognostic-related indicators of the two groups of B-ALL children(mainly including overall survival(OS),Event-free survival(EFS),Cumulative recurrence rate(CRR));? Analyze and compare the type and incidence of IKZF1 gene deletion in children with B-ALL;? Analyze the prognosis of children with IKZF1 gene deletion and non-deletion in children with B-ALL stratified at different risk levels;?Analyze the prognosis of children with IKZF1 gene deletion and non-deletion in BCR-ABL1 fusion gene positive and negative B-ALL children;? Multivariate analysis identify the prognostic risk factors of children with B-ALL.Results:1.Of the 367 children with B-ALL,there were 63 children(17.17%)in the IKZF1 gene deletion group.The male to female ratio was 1.74:1,and the median age was 6 years(September to 14 years).Compared with the children in the IKZF1 non-deleted group,the children in the IKZF1 gene-deleted group had a higher age of onset,initial leukocyte count,initial neutrophil count,and a higher incidence of BCR-ABL1 fusion gene positive.Prednisone response on day 8,bone marrow remission on day 15 were worse,minimal residual disease on day 33 was higher,and the differences were statistically significant(P<0.05);the immunophenotype in the IKZF1 gene-deleted group and the non-deleted group is mainly normal B and pre-B;IKZF1 gene deletion is most common in children with high-risk B-ALL,and low-risk B-ALL is most common in non-deleted IKZF1 gene group.2.Of the 367 B-ALL children,126 were positive for the fusion gene(34.33%)and the other were negative(65.67%).The most common fusion genes was TEL-AML1(13.35%).3.Of the 63 children with B-ALL with IKZF1 gene deletion,80.95%were localized large segment deletions and 12.70%were single exon deletions.In addition,a small number of non-localized deletions were seen.Exon 1-8(25.40%)and exon 4-7(19.05%)are the most common among the large deletions,and exon 1(6.35%)is the most common among single exon deletions.4.Among the 367 B-ALL children,the OS and EFS in the IKZF1 gene deletion group were lower than those in the non-deleted group(OS:69.80%vs.86.50%;EFS:57.10%vs.80.60%),while the CRR in the deletion group was higher than that in the non-deletion group(23.81%vs.8.88%).The differences between the two groups were statistically significant(P<0.05).5.For low-risk and medium-risk children,there were no significant differences in the OS,EFS,and CRR in the IKZF1 gene deletion group and non-deletion group in children with B-ALL(P>0.05);For high-risk children,the OS and EFS in the IKZF1 deletion group was lower than that in the non-deletion group(OS:66.70%vs.83.30%;EFS:50.00%vs.70.50%),while the CRR was higher than that in the non-deletion group(27.80%vs.14.10%).The differences between the two groups were statistically significant(P<0.05).6.Among the 367 children with B-ALL,30 children were positive for BCR-ABL1 fusion gene,of which 23(76.67%)were accompanied by IKZF1 gene deletion.For children with positive BCR-ABL1 fusion gene,there were no significant difference in OS,EFS,and CRR between the IKZF1 gene deletion group and the non-deletion group(P>0.05).For children with negative BCR-ABL1 fusion,the OS and EFS in the IKZF1 gene deletion group were lower than those in the non-deletion group,and the CRR was higher than that in the non-deletion group.The differences between the two groups were statistically significant(P<0.05).7.The results of multivariate analysis of the Cox proportional hazards regression model showed that IKZF1 gene deletion,initial white blood cell count(?50 × 109),and positive BCR-ABL1 fusion gene can be used as the independent risk factors for children with B-ALL.However,the effect of age and gender on the survival rate in children with B-ALL was not statistically significant(P>0.05).Conclusions:1.The incidence of IKZF 1 gene deletion is higher in children with positive BCR-ABL1 fusion gene than that in children with other type of B-ALL,and the most common type of the deletion is limited large fragment deletion.2.IKZF1 gene deletion may provide a new biological indicator for the division of risk stratification in children with B-ALL.3.IKZF1 gene deletion may be an independent risk factor for children with B-ALL.