IKZF3 polymorphisms contribute to the increased risk of acute lymphoblastic leukemia in children

Xu Yang; Lihua Yang; Annie Luo; Shanshan Liu; Xiaohong Zhang; Xiaoping Liu; Xiaodan Liu; Ailing Luo; Mansi Cai; Yaping Yan; Xuedong Wu; Ke Huang; Ling Xu; Hua Jiang

doi:10.1002/cncr.35129

IKZF3 polymorphisms contribute to the increased risk of acute lymphoblastic leukemia in children

Cancer. 2024 Mar 15;130(6):973-984. doi: 10.1002/cncr.35129. Epub 2023 Nov 29.

Authors

Xu Yang^{1

2}, Lihua Yang³, Annie Luo⁴, Shanshan Liu^{1

2}, Xiaohong Zhang¹, Xiaoping Liu^{1

2}, Xiaodan Liu^{1

5}, Ailing Luo^{1

2}, Mansi Cai^{1

2}, Yaping Yan^{1

2}, Xuedong Wu⁶, Ke Huang⁷, Ling Xu¹, Hua Jiang¹

Affiliations

¹ Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
² Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
³ Pediatric Center of Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Victoria College, University of Toronto, Toronto, Ontario, Canada.
⁵ Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China.
⁶ Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁷ Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

PMID: 38018448
DOI: 10.1002/cncr.35129

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. IKZF3 (IKAROS family zinc finger 3) is a hematopoietic-specific transcription factor, and it has been validated that it is involved in leukemia. However, the role of IKZF3 single-nucleotide polymorphisms (SNPs) remains unclear. In this case-control study, the authors investigated the association of IKZF3 SNPs with ALL in children.

Methods: Six IKZF3 reference SNPs (rs9635726, rs2060941, rs907092, rs12946510, rs1453559, and rs62066988) were genotyped in 692 patients who had ALL (cases) and in 926 controls. The associations between IKZF3 polymorphisms and ALL risk were determined using odds ratios (ORs) and 95% confidence intervals (CIs). The associations of rs9635726 and rs2060941 with the risk of ALL were further estimated by using false-positive report probability (FPRP) analysis. Functional analysis in silico was performed to evaluate the probability that rs9635726 and rs2060941 might influence the regulation of IKZF3.

Results: The authors observed that rs9635726C>T (adjusted OR, 1.49; 95% CI, 1.06-2.11; p = .023) and rs2060941G>T (adjusted OR, 1.51; 95% CI, 1.24-1.84; p = .001) were related to and increased risk of ALL in the recessive and dominant models, respectively. Furthermore, the associations of both rs9635726 (FPRP = .177) and rs2060941 (FPRP < .001) with ALL were noteworthy in the FPRP analysis. Functional analysis indicated that rs9635726 and rs2060941 might repress the transcription of IKZF3 by disrupting its binding to MLLT1, TAF1, POLR2A, and/or RAD21.

Conclusions: This study revealed that IKZF3 polymorphisms were associated with increased ALL susceptibility in children and might influence the expression of IKZF3 by disrupting its binding to MLLT1, TAF1, POLR2A, and/or RAD21. IKZF3 polymorphisms were suggested as a biomarker for childhood ALL.

Keywords: IKAROS family zinc finger 3 (IKZF3); acute lymphoblastic leukemia (ALL); children; single nucleotide polymorphisms (SNPs); susceptibility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Child
Genetic Predisposition to Disease
Genotype
Humans
Ikaros Transcription Factor / genetics
Polymorphism, Single Nucleotide*
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics

Substances

Ikaros Transcription Factor
IKZF3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding