Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA.
Leukemia. 2011 Apr;25(4):629-37. doi: 10.1038/leu.2010.325. Epub 2011 Jan 21.
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.
BMI-1 和 EZH2 是多梳组（PcG）蛋白，可维持干细胞的自我更新，在白血病中过表达。为了研究 PcG 蛋白作为白血病相关抗原和移植物抗白血病（GVL）效应的靶点的潜力，我们研究了 86 例慢性髓性白血病（CML）患者和 25 例人类白细胞抗原（HLA）-A0201（+）同胞供体在异基因干细胞移植（SCT）前获得的细胞。虽然 CML 患者经药物治疗后 CD34（+）细胞中 BMI-1 的过表达与预后不良相关，但我们发现相反，在接受 SCT 的 CML 患者中，BMI-1 的表达较高，相应地，其抑制靶标 CDKN2A 的表达较低，与无白血病生存改善相关。在 25 名供体中的 5 名（20%）和 19 名 HLA-A0201（+）CML 患者中的 8 名（42%）中检测到针对 BMI-1 肽的细胞毒性 T 淋巴细胞（CTL）反应。BMI-1 产生了更多的总和高亲和力免疫反应，比 EZH2 更具免疫原性。PcG 特异性 CTL 具有记忆表型，在短期培养中容易扩增，并在接受 PcG 特异性 CTL 阳性供体的受者中在 SCT 后检测到。CML CD34（+）祖细胞中 BMI-1 的高表达与天然 BMI-1 免疫反应相关。这些针对 PcG 蛋白的免疫反应可能靶向白血病干细胞，并与 GVL 控制疾病相关。
