Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein.

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)-A0201(+) 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-A0201(+) 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.
Authors	A S M Yong, N Stephens, G Weber, Y Li, B N Savani, R Eniafe, K Keyvanfar, R Kurlander, K Rezvani, A J Barrett
Journal	Leukemia (Leukemia) Vol. 25 Issue 4 Pg. 629-37 (Apr 2011) ISSN: 1476-5551 [Electronic] England
PMID	21252986 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	Antigens, CD34 BMI1 protein, human DNA-Binding Proteins HLA-A Antigens HLA-A*02:01 antigen HLA-A2 Antigen Nuclear Proteins Peptide Fragments Proto-Oncogene Proteins RNA, Messenger Repressor Proteins Transcription Factors EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Polycomb Repressive Complex 2 Polycomb Repressive Complex 1
Topics	Antigens, CD34 (metabolism) Cohort Studies DNA-Binding Proteins (genetics, metabolism) Enhancer of Zeste Homolog 2 Protein Enzyme-Linked Immunosorbent Assay Graft vs Host Disease (prevention & control) HLA-A Antigens HLA-A2 Antigen Humans Immunophenotyping Leukemia, Myelogenous, Chronic, BCR-ABL Positive (immunology, metabolism, therapy) Nuclear Proteins (genetics, immunology, metabolism) Peptide Fragments (immunology, metabolism) Polycomb Repressive Complex 1 Polycomb Repressive Complex 2 Proto-Oncogene Proteins (genetics, immunology, metabolism) RNA, Messenger (genetics) Repressor Proteins (genetics, immunology, metabolism) Reverse Transcriptase Polymerase Chain Reaction Stem Cell Transplantation Survival Rate T-Lymphocytes, Cytotoxic (immunology) Transcription Factors (genetics, metabolism) Transplantation, Homologous Treatment Outcome

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