The Ikaros1, IKZF1, risk locus for Acute Lymphoblastic Leukemia (ALL) at chromosome 7p12.2 regulates the expression of the FIGNL1 gene

Abstract

ALL, the most common pediatric cancer, originates from progenitor B-cells in ~85% of cases. IKAROS Family Zinc Finger 1 (IKZF1) is an important locus for ALL. Our goal was to identify the functional variants, thereby nominating a potential causal mechanism for ALL. We evaluated all 27 genetic polymorphisms in disequilibrium at r2>0.8 with the tag, the most highly associated risk variant at IKZF1 locus. They map to intron 7, 3′ UTR and 3′ flanking sequence of IKZF1. Fidgetin-like protein 1 (FIGNL1) is 45,524 bases from the tag variant and is nominated by eQTL and DNA looping data along with IKZF1 as possible targets. Epstein-Barr virus (EBV) transformed GM12878 cells were transduced with lentiviral vectors for stable expression of fusion proteins dead (d) Cas9-VP64 and activator MS2-p65-HSF1 (synergistic activation mediator (SAM) system). We designed 27 single guide (sg) RNAs, one for each of the 27 variants and evaluated expression perturbation in cells transfected with pools and individual sgRNA. Expression of FIGNL1, but not IKZF1, was convincingly altered in this system. The reduction of FIGNL1 expression by ~50% was isolated to two neighboring variants separated by 1 kb. The risk allele at these variants increases FIGNL1 expression in wild type cells, however in EBV transformed B-cells FIGNL1 expression is decreased. Other data show that the EBV encoded DNA binding co-factor EBNA3C binds at or very near this locus in EBV transformed B cells. Our results nominate two closely located SNPs in the last intron of IKZF1 as potentially causal variants, controlling the expression of FIGNL1, which ordinarily participates in homologous recombination during DNA double-strand break repair, maintenance of genomic stability and prevention of cancer.

High frequency of the risk allele of rs4132601 and rs11978267 from the IKZF1 gene in indigenous Mexican population

“…One proposed explanation is that they could modify the expression of FIGNL1 , due to these SNPs have been described as expression quantitative trait loci (eQTL), which are genomic loci that regulate the levels expression of the mRNA of the neighbor gene FIGNL1 , an important gene involved in maintenance of genomic stability, in DNA double‐strand break (DBS) repair, via homologous recombination and cancer prevention. Likewise, this gene regulates the osteoblast proliferation and differentiation, and recently, has been associated with BCP‐ALL (Jayaram Laurynenka et al, 2020; Vijayakrishnan et al, 2018). Another hypothesis is that they could indirectly modify the gene expression when both polymorphisms are in linkage disequilibrium, as was previously described by Lopes et al, (2017), who suggest that haplotypes carrying variant genotypes of rs4132601 and rs11978267 may be related with leukemic transformation such as when IKZF1 deletions are present.…”