Significance Of IKZF1 Gene Copy Number Abnormalities In B-lineage Acute Lymphoblastic Leukemia In Children

Objective:To identify IKZF1 gene copy number abnormalities in children with B-lineage acute lymphoblastic leukemia (B-ALL), reveal its clinical features, clear the value of IKZF1 gene copy number abnormalities, and provide a theoretical basis for the selection of chemotherapy protocol in children with B-ALL accompanied by IKZF1 gene copy number abnormalities in the future.Methods:93 children with newly diagnosed B-ALL were detected IKZF1 gene copy number abnormalities by multiplex ligation dependent probe amplification (MLPA). The association between IKZF1 copy number abnormalities and characteristics as well as prognosis (eg, sex, age, CNS status, white blood cell count, early treatment response, MRD group, risk category, genetic subtype, disease-free survival (DFS) and overall survival (OS)) of these 93 children was analyzed retrospectively. The Cox multiple regression analysis was used to determine the risk factors of DFS and OS in children with B-ALL.Results:1. The rate of IKZF1 deletion among children with B-ALL was 19.4% (18/93), in which 3 had complete deletions of IKZF1’s 8 exons,9 had deletion of only exon I,4 had deletions of exons 4-7,1 had deletions of exons 2-7 and I had deletions of exons 3-7.2.3 cases relapsed in IKZF1 deletion group of B-ALL with recurrence rate of 16.7%(3/18), all in high-risk group and of bone marrow relapse in which 2 children dead (the time from relapse to death was 68 and 113 days, respectively).7 cases relapsed (4 cases of bone marrow relapse,1 case of testicular relapse and 2 cases of CNS relapse) in no IKZF1 deletion group of B-ALL with recurrence rate of 9.3% (7/75), in which 1 of low-risk group (testicular relapse),2 of middle-risk group (I case of bone marrow relapse,1 case of CNS relapse),4 of high-risk group (3 cases of bone marrow relapse,1 case of CNS relapse). Among these relapsed children in no IKZF1 deletion group,1 case of CNS relapsed in middle-risk group (the time from relapse to death was 65 days) and 2 cases of bone marrow relapsed in high-risk group dead (the time from relapse to death was 78 and 121 days, respectively).3. No significant difference was found in sex, age, early treatment response, CNS status and risk category based on the CCLG-ALL-2008 protical between IKZF1 deletion group and no IKZF1 deletion group, but children with IKZF1 deletion were significantly more frequently with a higher WBC count at diagnosis (P= 0.019) and high risk based on MRD (P= 0.041).4. The median follow-up was 347 days, Kaplan-Meier analysis showed IKZF1 deletion group’s DFS was slightly lower, but without statistically significant (the DFS at 300 days of these two groups were 0.798 ± 0.206 vs 0.925 ± 0.073, P= 0.437). So was the OS of IKZF1 deletion group (the DFS at 300 days of these two groups were 0.929±0.135 vs 0.985±0.029, P= 0.329).5. Cox multiple regression analysis showed that BCR/ABL1 status, MLLr, the finnal risk group and early treatment response affected the DFS of children with B-ALL significantly (P<0.05), while for the OS it was BCR/ABL1 status, MLLr and the finnal risk group (P<0.05). Meanwhile the more pwoerful influence factors of DFS and OS were BCR/ABL1 status and MLLr.Conclusions:1. The dominant negative (DN) subtypes of IKZF1 (eg,IK6) may be less commen in children than adults, and each exon deletion of IKZF1 may valuable for children.2. IKZF1 deletion probably affected the cancer bone marrow stem cells in these B-ALL chlidren, meanwhile more attention should be paid to the chlidren in high-risk group with IKZF1 deletion for the high recurrence and mortality rate.3.IKZF1 deletion may be one of the reasons for poor prognosis in children with B-ALL and high MRD or high WBC.4. It would be gradually clear the value for prognosis of IKZF1 deletion with the extension of the follow-up time.5. The genetic subtype was still the major factor affected the prognosis of children with B-ALL.6. The IKZF1 deletion should be used as a risk factor for risk stratification in order to guide the treatment, at the same time, for the B-ALL chlidren with IKZF1 deletion, the maintenance treatment should be changed to improve outcomes, such as: increase the drug dose, add chemotherapeutic drugs or prolonge treatment time, however it should be based on children’s specific situation (eg, drug tolerance).7.The MLPA applied to identify IKZF1 gene copy number abnormalities is simple, can be used for the detection of IKZF1 in patients with ALL before treatment and even for the monitoring of MRD.