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. 2011 Apr;25(4):629-37.
doi: 10.1038/leu.2010.325. Epub 2011 Jan 21.

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

A S M Yong  1 , N Stephens, G Weber, Y Li, B N Savani, R Eniafe, K Keyvanfar, R Kurlander, K Rezvani, A J Barrett
Affiliations

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

A S M Yong et al. Leukemia. 2011 Apr.

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.

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Conflict of interest statement

Conflict of interest

The authors have no competing financial interests in relation to the work described.

Figures

Figure 1
Figure 1. BMI-1 expression and post-transplant outcome
Probability of leukemia-free survival (A), overall survival (B) and transplant-related death (C), in CP-CML. Groups are segregated according to the median (M) values of BMI-1 expression.
Figure 1
Figure 1. BMI-1 expression and post-transplant outcome
Probability of leukemia-free survival (A), overall survival (B) and transplant-related death (C), in CP-CML. Groups are segregated according to the median (M) values of BMI-1 expression.
Figure 1
Figure 1. BMI-1 expression and post-transplant outcome
Probability of leukemia-free survival (A), overall survival (B) and transplant-related death (C), in CP-CML. Groups are segregated according to the median (M) values of BMI-1 expression.
Figure 2
Figure 2. BMI-1-specific cytotoxic T lymphocytes are polyfunctional
Representative dot plots from CML patient UPN 25 showing ex-vivo immune responses to BMI-T and EZH-Y peptides using detection of interferon- (IFN)-γ, CD107a degranulation, tumor necrosis factor (TNF)-α and interleukin (IL)-2. A positive response is defined as at least (a) two-fold background (negative control) and (b) 0.05% CD8+ population. Low avidity response to 10μM BMI-T peptide is detected with IFN-γ and TNF-α production. High avidity TNF-α response to 0.1μM BMI-T peptide is accompanied by CD107a degranulation. In comparison, low avidity response to 10μM EZH-Y peptide is manifest with IFN-γ production alone.
Figure 3
Figure 3. Immune responses to BMI-1-specific peptides detected post-transplant
Representative immune responses to BMI-T and BMI-C peptides in CML patient UPN 365 at D120 post-transplant. (A) Phenotypic characterization of BMI-1- specific and CMV-specific cytotoxic T lymphocytes (CTLs) using dextramers, with HIV dextramers as negative controls (EM= effector memory; CM= central memory; TDEM = terminally differentiated effector memory CTLs) (B) ELISPOT short-term expansion of BMI-1-specific CTLs, with interferon (IFN)-γ production to BMI-T and BMI-C peptides with similar avidity as in the donor pre-transplant. Numbers below wells refer to IFN-γ spots.
Figure 3
Figure 3. Immune responses to BMI-1-specific peptides detected post-transplant
Representative immune responses to BMI-T and BMI-C peptides in CML patient UPN 365 at D120 post-transplant. (A) Phenotypic characterization of BMI-1- specific and CMV-specific cytotoxic T lymphocytes (CTLs) using dextramers, with HIV dextramers as negative controls (EM= effector memory; CM= central memory; TDEM = terminally differentiated effector memory CTLs) (B) ELISPOT short-term expansion of BMI-1-specific CTLs, with interferon (IFN)-γ production to BMI-T and BMI-C peptides with similar avidity as in the donor pre-transplant. Numbers below wells refer to IFN-γ spots.
Figure 4
Figure 4. Avidity of CD8+ T-cell responses to peptides derived from polycomb group proteins (PcG) BMI-1 and EZH2
High- and low-avidity CD8+ T-cell responses are determined by stimulation with 0.1μM or 10μM peptide respectively(28, 31). Results are shown as the ratios of high- to low-avidity T-cell responses from healthy donors (black circles), patients pre-(open circles), and post-allogeneic stem cell transplant (post-SCT) (red circles). Ratios are calculated as IFN-γ+ CD8+ T-cells (%) with 0.1μM peptide/IFN-γ+ CD8+ T-cells (%) with 10μM peptide. Bars represent the median high/low avidity ratio for each peptide. Symbols above the dashed line are samples with majority high avidity responses.
Figure 5
Figure 5. Peptide specific CD8+ T-cell expansion in response to leukemia-associated antigens (LAAs) in healthy donors
(A) Specific cytotoxic T lymphocyte (CTL) expansion following incubation with BMI-T, BMI-C, EZH-Y, EZH-S, WT1 and PR1 peptides was assessed simultaneously in eight healthy blood donors (HD) at weekly intervals using ELISPOT assay. Individual samples are plotted along the x-axis and the maximal response observed during this time period for each LAA is plotted on the y-axis. (B) Pattern of longitudinal expansion of individual LAA-specific CTLs in representative sample HD2 over 6 weeks. The y-axis denotes the maximum number of interferon (IFN)-γ producing spots positive per 25,000 CD8+ cells plated.
Figure 5
Figure 5. Peptide specific CD8+ T-cell expansion in response to leukemia-associated antigens (LAAs) in healthy donors
(A) Specific cytotoxic T lymphocyte (CTL) expansion following incubation with BMI-T, BMI-C, EZH-Y, EZH-S, WT1 and PR1 peptides was assessed simultaneously in eight healthy blood donors (HD) at weekly intervals using ELISPOT assay. Individual samples are plotted along the x-axis and the maximal response observed during this time period for each LAA is plotted on the y-axis. (B) Pattern of longitudinal expansion of individual LAA-specific CTLs in representative sample HD2 over 6 weeks. The y-axis denotes the maximum number of interferon (IFN)-γ producing spots positive per 25,000 CD8+ cells plated.
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