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, N. Stephens, G. Weber, Y. Li, B. N. Savani, R. Eniafe, K. Keyvanfar, R. Kurlander, K. Rezvani, A. J. Barrett

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)629-637
Number of pages9
JournalLeukemia
Volume25
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • BMI-1
  • chronic myeloid leukemia
  • graft-versus-leukemia effect
  • leukemia-associated antigens

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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