Abstract
BMI-1 and EZH2 are polycomb group (PcG) proteins that maintain self-renewal of stem cells, and are overexpressed in leukemia. To investigate the potential of PcG proteins as leukemia-associated antigens, and as targets for graft-versus-leukemia (GVL) effects, we studied cells obtained from 86 patients with chronic myeloid leukemia (CML) and 25 human leukocyte antigen (HLA)-A*0201(+) sibling donors collected before allogeneic stem cell transplantation (SCT). Although BMI-1 overexpression in CD34(+) cells of CML patients treated with pharmacotherapy is associated with poor prognosis, we found, conversely, that in CML patients treated with SCT, a higher expression of BMI-1, and correspondingly a lower expression of its target for repression, CDKN2A, is associated with improved leukemia-free survival. Cytotoxic T-lymphocyte (CTL) responses to the BMI-1 peptide were detected in 5 of 25 (20%) donors, and in 8 of 19 (42%) HLA-A*0201(+) CML patients. BMI-1 generated more total and high-avidity immune responses, and was more immunogenic than EZH2. PcG-specific CTLs had a memory phenotype, were readily expanded in short-term cultures and were detected after SCT in recipients of PcG-specific CTL-positive donors. A higher BMI-1 expression in CML CD34(+) progenitors was associated with native BMI-1 immune responses. These immune responses to PcG proteins may target leukemia stem cells and have relevance for disease control by GVL.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Antigens, CD34 / metabolism
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Cohort Studies
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enhancer of Zeste Homolog 2 Protein
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Enzyme-Linked Immunosorbent Assay
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Graft vs Host Disease / prevention & control*
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HLA-A Antigens
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HLA-A2 Antigen
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Humans
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Immunophenotyping
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy*
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Nuclear Proteins / metabolism*
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Polycomb Repressive Complex 1
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Polycomb Repressive Complex 2
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology*
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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Repressor Proteins / genetics
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Repressor Proteins / immunology*
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Repressor Proteins / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Stem Cell Transplantation*
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Survival Rate
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T-Lymphocytes, Cytotoxic / immunology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transplantation, Homologous
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Treatment Outcome
Substances
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Antigens, CD34
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BMI1 protein, human
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DNA-Binding Proteins
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HLA-A Antigens
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HLA-A*02:01 antigen
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HLA-A2 Antigen
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Nuclear Proteins
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Peptide Fragments
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Proto-Oncogene Proteins
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RNA, Messenger
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Repressor Proteins
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Transcription Factors
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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Polycomb Repressive Complex 1