TY - JOUR
T1 - 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
AU - Yong, A. S.M.
AU - Stephens, N.
AU - Weber, G.
AU - Li, Y.
AU - Savani, B. N.
AU - Eniafe, R.
AU - Keyvanfar, K.
AU - Kurlander, R.
AU - Rezvani, K.
AU - Barrett, A. J.
N1 - Funding Information:
This research was supported by the Intramural Research Program of the National Institutes of Health, at the NHLBI.
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - BMI-1
KW - chronic myeloid leukemia
KW - graft-versus-leukemia effect
KW - leukemia-associated antigens
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U2 - 10.1038/leu.2010.325
DO - 10.1038/leu.2010.325
M3 - Article
C2 - 21252986
AN - SCOPUS:79954443802
SN - 0887-6924
VL - 25
SP - 629
EP - 637
JO - Leukemia
JF - Leukemia
IS - 4
ER -