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

BMI-1 and EZH2 are polycomb group (PcG) proteins which maintain self-renewal of stem cells, and are overexpressed in leukemia. To investigate the potential of PcG proteins as leukemia-associated antigens, and targets for graft-versus-leukemia (GVL) effects, we studied cells from 86 chronic myeloid leukemia (CML) patients and 25 HLA-A*0201(+) sibling donors collected prior to 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 lower expression of its target for repression, CDKN2A, is associated with improved leukemia-free survival. Cytotoxic T lymphocyte (CTL) responses to BMI-1 peptide were detected in 5 of 25 (20%) donors, and 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 memory phenotype, were readily expanded in short-term cultures, and were detected post-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.