+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn

+ Translate
+ Recently Requested

A Single Nucleotide Polymorphism in Proteinase 3 That Codes for HLA-A2-Binding Peptides Protects Against Development of Acute Myelogenous Leukemia

A Single Nucleotide Polymorphism in Proteinase 3 That Codes for HLA-A2-Binding Peptides Protects Against Development of Acute Myelogenous Leukemia

Blood 100(11): Abstract No 2194, November 16

We have previously shown that cytotoxic T lymphocytes (CTL) with specificity for PR1, a 9 amino acid HLA-A2-restricted peptide derived from proteinase 3, contribute to cytogenetic remission in chronic myelogenous leukemia (CML) patients treated with interferon-alpha (IFN). Since proteinase 3 is a leukemia-associated tumor antigen there are likely to be other epitopes may be important for eliciting an anti-leukemia immune response. We have identified a coding region single nucleotide polymorphism (cSNP) at position 3393 in exon 3 of the proteinase 3 gene (A or G base change) that codes for a nonamer peptide fragment with either a valine (V) or isoleucine (I), respectively, at position 119 of the protein, and we have shown that both peptides bind equally well to HLA-A2. These peptides have been named PR7V and PR7I, respectively. Furthermore, we have shown that the population gene frequency of both alleles is close to 0.5 (using allele-specific PCR analyses). To determine whether this cSNP codes for a potential minor histocompatibility antigen (mHA), we first sought to elicit T cells with PR7V and PR7I peptide specificity. Healthy donor lymphocytes from two patients that were homozygous for either the A or G polymorphism were stimulated weekly with PR7V- or PR7I-pulsed T2 cells with 20 U/ml IL-2. At the end of 4 weeks in culture, the resulting T cell lines were tested for peptide specificity in standard 4-hour cytotoxicity assays using peptide-pulsed T2 cells as targets. The lymphocytes that were A/A homozygous (coding PR7V) showed 28.6% specific lysis of PR7I-pulsed T2 cells, but only 17.2% of PR7V-pulsed T2 cells at E:T of 12:1. Conversely, lymphocytes that were G/G homozygous (coding PR7I) showed no specific lysis of PR7V-pulsed T2 cells. These preliminary results show the potential of this cSNP to code for a mHA, although further experiments are underway to confirm this. To determine whether the polymorphism correlated with disease occurrence in patients with myeloid leukemias, we performed genotyping on 161 individuals using allele-specific PCR: 46 healthy donors (39 HLA-A2+, 7 HLA-A2-), 18 CML patients, 65 AML patients, and 32 CLL patients. In the healthy donor population, the gene frequency of A (P(A)) is estimated at 0.63, and P(G) is 0.37. In the CML and CLL patients, P(A) was found to be 0.47 and 0.41, respectively, which is not statistically different from the healthy donor population. However, P(A) in the AML patients was found to be 0.33, which is significantly lower than the expected P(A) of 0.63 (p = 0.01). More importantly, none of the 65 AML patients were homozygous A/A, whereas 10 of 46 healthy donors were A/A homozygous (p = 0.0001). Interestingly, neither the HLA-A2+ nor the HLA-A2- healthy donors were A/A homozygous, which suggests that both PR7V and PR7I might be recognized by T cells, which might protect against the development of AML in the host by a host-mediated immune response. Alternatively, proteinase 3 may be important in leukemagenesis or maintenance of the leukemia phenotype, which has been shown previously, and that the G polymorphism codes for a dysfunctional protein with leukemagenic potential. Both hypotheses are currently being pursued in the laboratory.

(PDF emailed within 1 workday: $29.90)

Accession: 034279576

Download citation: RISBibTeXText

Related references

A genome-wide single-nucleotide polymorphism-array can improve the prognostic stratification of the core binding factor acute myeloid leukemia. American Journal of Hematology 87(10): 961-968, 2012

Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia. Haematologica 95(9): 1481-1488, 2012

Whole genome association study in leukemia: Frequent loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) in acute myeloid leukemia with a normal karyotype. 2007

Single-nucleotide polymorphism array-based karyotyping of acute promyelocytic leukemia. Plos One 9(6): E100245, 2015

Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis: A single center experience of 296 cases. Genes, Chromosomes and Cancer 57(11): 604-607, 2018

Single nucleotide polymorphism genomic arrays analysis of t(8;21) acute myeloid leukemia cells. Haematologica 94(9): 1301-1306, 2009

Association of single nucleotide polymorphism of methylenetetrahydrofolate reductase gene with susceptibility to acute leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 30(4): 451-455, 2014

Homozygosity for the C-->T polymorphism at nucleotide 46 in the 5' untranslated region of the factor XII gene protects from development of acute coronary syndrome. British Journal of Haematology 115(4): 1007-1009, 2002

Ring chromosome 5 in acute myeloid leukemia defined by whole-genome single nucleotide polymorphism array. Annals of Laboratory Medicine 32(4): 307-311, 2012

Association of single nucleotide polymorphism of reduced folate carrier gene with susceptibility to acute leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 28(4): 446-449, 2011

Analysis of a 452C/T single nucleotide polymorphism in γ-glutamyl hydrolase gene in children with acute leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 29(3): 352-355, 2012

Study of mutation and single nucleotide polymorphism of PDGFRbeta and SHIP gene in acute myeloid leukemia. Zhonghua Xue Ye Xue Za Zhi 27(6): 383-385, 2006

No prognostic impact of the WT1 gene single nucleotide polymorphism rs16754 in pediatric acute myeloid leukemia. Journal of Clinical Oncology 28(28): E523-6; Author Reply E527-E528, 2010

Single-nucleotide polymorphism-array improves detection rate of genomic alterations in core-binding factor leukemia. Medical Oncology 30(2): 579, 2013

Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Haematologica 96(10): 1488-1495, 2012