Investigation of NF-κB-94ins/del ATTG and CARD8 (rs2043211) Gene Polymorphism in Acute Lymphoblastic Leukemia

Chen Zhang,Daoxin Ma,Fengjiao Han,Xiang Hu,Chaoqin Zhong,Chunyan Ji,Mingqiang Hua,Xueyun Zhao,Yufeng Shi,Jie Yu,Ruiqing Wang

doi:10.3389/fendo.2019.00501

Abstract

NLRP3 inflammasome has been widely implicated in the development and progression of various hematological diseases. However, how NLRP3 inflammasome contributes to the pathogenesis and clinical features of acute lymphoblastic leukemia (ALL) is still unknown. Here, in ALL patients' bone marrow, we investigated the single-nucleotide polymorphisms (SNPs) and expression of NLRP3 inflammasome related genes, NF-κB, NLRP3, IL-1β, IL-18, Caspase-1, and ASC. A total of 308 ALL patients and 300 healthy participants were included in this study. D allele and DD genotype under codominant model of NF-κB-94ins/del ATTG were showed as a protective factor in susceptibility of ALL. As for CARD8 (rs2043211), AT/TT genotype under dominant model and TT genotype under codominant model greatly increased the ALL susceptibility. We further studied the relationship between NLRP3 inflammasome genetic polymorphisms and clinical relevance. The results showed that DD genotype of NF-κB-94 ins/del ATTG and AT/TT genotype of CARD8 (rs2043211) contributed to lower WBC count and T-cell immunophenotype, respectively. Moreover, we also found that AT and TT genotypes of CARD8 (rs2043211), GT and TT genotypes of IL-1β (rs16944), and TT genotype of IL-18 (rs1946518) were associated with higher mRNA expression of NLRP3 inflammasome related genes and secretion of downstream cytokines. In conclusion, NF-κB-94 ins/del ATTG and CARD8 (rs2043211) genotypes might serve as novel biomarkers and potential targets for ALL.

Highlights

Acute lymphoblastic leukemia (ALL) is a clonal disorder driven by accumulation of progenitor cells in the peripheral blood and bone marrow [1, 2]
We examined single-nucleotide polymorphisms (SNPs) of NLRP3 inflammasome related genes: NFκB (-94 ins/del ATTG), CARD8, IL-18, and IL-1β in 308 acute lymphoblastic leukemia (ALL) patients and 300 healthy controls
For 94 ins/del ATTG in nuclear factor (NF)-κB, the frequency of D allele was lower in ALL patients compared to controls (37.8 vs. 43.5%), and it was significantly associated with ALL susceptibility (OR = 0.790, 95% confidence interval (95% CI) 0.628–0.994, p = 0.044)

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is a clonal disorder driven by accumulation of progenitor cells in the peripheral blood and bone marrow [1, 2]. Adult ALL accounts for only 20% of leukemia, it is more common in childhood acute leukemia (80% of cases). Through traditional chemotherapy, the cure rate of ALL can only reach about 20–40% in adults compared to 80% in children [3, 4]. Adult patients present higher risk features at diagnosis, more likely to come up with chemotherapy resistance and higher relapse rate after complete remission (CR) [5]. Multiple studies reported that the genetic variants of some metabolism and inflammation related genes contribute to ALL pathogenesis and prognosis [6, 7].

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Results

Conclusion