title: Altered HLA Class I Profile Associated with Type A/D Nucleophosmin Mutation Points to Possible Anti-Nucleophosmin Immune Response in Acute Myeloid Leukemia.
abstract: Nucleophosmin 1 (NPM1) mutations are frequently found in patients with acute myeloid leukemia (AML) and the newly generated sequences were suggested to induce immune response contributing to the relatively favorable outcome of patients in this AML subset. We hypothesized that if an efficient immune response against mutated nucleophosmin can be induced in vivo, the individuals expressing HLA alleles suitable for presenting NPM-derived peptides should be less prone to developing AML associated with NPM1 mutation. We thus compared HLA class I frequencies in a cohort of patients with mutated NPM1 (63 patients, NPMc+), a cohort of patients with wild-type NPM1 (94 patients, NPMwt) and in normal individuals (large datasets available from Allele Frequency Net Database). Several HLA allelic groups were found to be depleted in NPMc+ patients, but not in NPMwt compared to the normal distribution. The decrease was statistically significant for HLA B(*)07, B(*)18, and B(*)40. Furthermore, statistically significant advantage in the overall survival was found for patients with mutated NPM1 expressing at least one of the depleted allelic groups. The majority of the depleted alleles were predicted to bind potent NPM-derived immunopeptides and, importantly, these peptides were often located in the unmutated part of the protein. Our analysis suggests that individuals expressing specific HLA allelic groups are disposed to develop an efficient anti-AML immune response thanks to aberrant cytoplasmic localization of the mutated NPM protein.
authors.affiliation: Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kuželová
authors.affiliation: Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Brodská
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Ota
authors.initials: O
authors.lastname: Fuchs
authors.affiliation: Department of HLA, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Dobrovolná
authors.affiliation: Clinical Department, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Soukup
authors.affiliation: Clinical Department, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Cetkovský
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007109:Immunity; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D000090243:Nucleophosmin; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D016019:Survival Analysis
chemical_list: D015395:Histocompatibility Antigens Class I; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D010455:Peptides; D000090243:Nucleophosmin