Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen

Sebastian Ochsenreither, Ravindra Majeti, Thomas Schmitt, Derek Stirewalt, Ulrich Keilholz, Keith R. Loeb, Brent Wood, Yongiae E. Choi, Marie Bleakley, Edus H. Warren, Michael Hudecek, Yoshiki Akatsuka, Irving L. Weissman, Philip D. Greenberg

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Targeted T-cell therapy is a potentially less toxic strategy than allogeneic stem cell transplantation for providing a cytotoxic antileukemic response to eliminate leukemic stem cells (LSCs) in acute myeloid leukemia (AML). However, this strategy requires identification of leukemia-associated antigens that are immunogenic and exhibit selective high expression in AML LSCs. Using microarray expression analysis of LSCs, hematopoietic cell subpopulations, and peripheral tissues to screen for candidate antigens, cyclin-A1 was identified as a candidate gene. Cyclin-A1 promotes cell proliferation and survival, has been shown to be leukemogenic in mice, is detected in LSCs of more than 50% of AML patients, and is minimally expressed in normal tissues with exception of testis. Using dendritic cells pulsed with a cyclin-A1 peptide library, we generated T cells against several cyclin-A1 oligopeptides. Two HLA A&z.ast;0201-restricted epitopes were further characterized, and specific CD8 T-cell clones recognized both peptide-pulsed target cells and the HLA A&z.ast;0201-positive AML line THP-1, which expresses cyclin-A1. Furthermore, cyclin-A1-specific CD8 T cells lysed primary AML cells. Thus, cyclin-A1 is the first prototypic leukemia-testis-antigen to be expressed in AML LSCs. The pro-oncogenic activity, high expression levels, and multitude of immunogenic epitopes make it a viable target for pursuing T cell-based therapy approaches.

Original languageEnglish
Pages (from-to)5492-5501
Number of pages10
JournalBlood
Volume119
Issue number23
DOIs
Publication statusPublished - 07-06-2012

Fingerprint

Cyclin A1
Myeloid Progenitor Cells
Testicular Neoplasms
Stem cells
Acute Myeloid Leukemia
T-cells
Antigens
T-Lymphocytes
Stem Cells
HLA-A Antigens
Cell- and Tissue-Based Therapy
Testis
Epitopes
Leukemia
Tissue
Peptide Library
Oligopeptides
Poisons
Cell proliferation
Stem Cell Transplantation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ochsenreither, S., Majeti, R., Schmitt, T., Stirewalt, D., Keilholz, U., Loeb, K. R., ... Greenberg, P. D. (2012). Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. Blood, 119(23), 5492-5501. https://doi.org/10.1182/blood-2011-07-365890
Ochsenreither, Sebastian ; Majeti, Ravindra ; Schmitt, Thomas ; Stirewalt, Derek ; Keilholz, Ulrich ; Loeb, Keith R. ; Wood, Brent ; Choi, Yongiae E. ; Bleakley, Marie ; Warren, Edus H. ; Hudecek, Michael ; Akatsuka, Yoshiki ; Weissman, Irving L. ; Greenberg, Philip D. / Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. In: Blood. 2012 ; Vol. 119, No. 23. pp. 5492-5501.
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abstract = "Targeted T-cell therapy is a potentially less toxic strategy than allogeneic stem cell transplantation for providing a cytotoxic antileukemic response to eliminate leukemic stem cells (LSCs) in acute myeloid leukemia (AML). However, this strategy requires identification of leukemia-associated antigens that are immunogenic and exhibit selective high expression in AML LSCs. Using microarray expression analysis of LSCs, hematopoietic cell subpopulations, and peripheral tissues to screen for candidate antigens, cyclin-A1 was identified as a candidate gene. Cyclin-A1 promotes cell proliferation and survival, has been shown to be leukemogenic in mice, is detected in LSCs of more than 50{\%} of AML patients, and is minimally expressed in normal tissues with exception of testis. Using dendritic cells pulsed with a cyclin-A1 peptide library, we generated T cells against several cyclin-A1 oligopeptides. Two HLA A&z.ast;0201-restricted epitopes were further characterized, and specific CD8 T-cell clones recognized both peptide-pulsed target cells and the HLA A&z.ast;0201-positive AML line THP-1, which expresses cyclin-A1. Furthermore, cyclin-A1-specific CD8 T cells lysed primary AML cells. Thus, cyclin-A1 is the first prototypic leukemia-testis-antigen to be expressed in AML LSCs. The pro-oncogenic activity, high expression levels, and multitude of immunogenic epitopes make it a viable target for pursuing T cell-based therapy approaches.",
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Ochsenreither, S, Majeti, R, Schmitt, T, Stirewalt, D, Keilholz, U, Loeb, KR, Wood, B, Choi, YE, Bleakley, M, Warren, EH, Hudecek, M, Akatsuka, Y, Weissman, IL & Greenberg, PD 2012, 'Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen', Blood, vol. 119, no. 23, pp. 5492-5501. https://doi.org/10.1182/blood-2011-07-365890

Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. / Ochsenreither, Sebastian; Majeti, Ravindra; Schmitt, Thomas; Stirewalt, Derek; Keilholz, Ulrich; Loeb, Keith R.; Wood, Brent; Choi, Yongiae E.; Bleakley, Marie; Warren, Edus H.; Hudecek, Michael; Akatsuka, Yoshiki; Weissman, Irving L.; Greenberg, Philip D.

In: Blood, Vol. 119, No. 23, 07.06.2012, p. 5492-5501.

Research output: Contribution to journalArticle

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AU - Ochsenreither, Sebastian

AU - Majeti, Ravindra

AU - Schmitt, Thomas

AU - Stirewalt, Derek

AU - Keilholz, Ulrich

AU - Loeb, Keith R.

AU - Wood, Brent

AU - Choi, Yongiae E.

AU - Bleakley, Marie

AU - Warren, Edus H.

AU - Hudecek, Michael

AU - Akatsuka, Yoshiki

AU - Weissman, Irving L.

AU - Greenberg, Philip D.

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