Abstract
Immunotherapy targeting leukemia-associated antigens has shown promising results. Because of the heterogeneity of leukemia, vaccines with a single peptide have elicited only a limited immune response. Targeting several peptides together elicited peptide-specific cytotoxic T lymphocytes (CTLs) in leukemia patients, and this was associated with clinical responses. Thus, the discovery of novel antigens is essential. In the current study, we investigated cyclin E as a novel target for immunotherapy. Cyclin E1 and cyclin E2 were found to be highly expressed in hematologic malignancies, according to reverse transcription polymerase chain reaction and western blot analysis. We identified two HLA-A*0201 binding nonameric peptides, CCNE1M from cyclin E1 and CCNE2L from cyclin E2, which both elicited the peptide-specific CTLs. The peptide-specific CTLs specifically kill leukemia cells. Furthermore, CCNE1M and CCNE2L CTLs were increased in leukemia patients who underwent allogeneic hematopoietic stem cell transplantation, and this was associated with desired clinical outcomes. Our findings suggest that cyclin E1 and cyclin E2 are potential targets for immunotherapy in leukemia.
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References
Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007;25:1908–15.
Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006;368:1894–907.
Russell JA, Larratt L, Brown C, Turner AR, Chaudhry A, Booth K, et al. Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: influence of stem cell source on outcome. Bone Marrow Transplant. 1999;24:1177–83.
Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989;73:1720–8.
Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, et al. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006;24:5742–9.
Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495–500.
Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, et al. Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood. 1996;88:2450–7.
Molldrem JJ, Clave E, Jiang YZ, Mavroudis D, Raptis A, Hensel N, et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood. 1997;90:2529–34.
Molldrem JJ, Lee PP, Wang C, Champlin RE, Davis MM. A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. Cancer Res. 1999;59:2675–81.
Qazilbash MH, Wieder E, Thall PF, Wang X, Rios R, Lu S, et al. PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies. Leukemia. 2017;31:697–704.
Oka Y, Tsuboi A, Nishida S, Hosen N, Nakata J, Hashii Y. et al. [WT1 peptide-based immunotherapy for the treatment of malignancies: focusing on hematological neoplasms]. Rinsho Ketsueki. 2011;52:235–42.
Oka Y, Tsuboi A, Fujiki F, Li Z, Nakajima H, Hosen N, et al. WT1 peptide vaccine as a paradigm for "cancer antigen-derived peptide"-based immunotherapy for malignancies: successful induction of anti-cancer effect by vaccination with a single kind of WT1 peptide. Anticancer Agents Med Chem. 2009;9:787–97.
Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J, et al. Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood. 2008;111:236–42.
Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, et al. Cyclin E and survival in patients with breast cancer. N Engl J Med. 2002;347:1566–75.
Mishina T, Dosaka-Akita H, Hommura F, Nishi M, Kojima T, Ogura S, et al. Cyclin E expression, a potential prognostic marker for non-small cell lung cancers. Clin Cancer Res. 2000;6:11–6.
Sakaguchi T, Watanabe A, Sawada H, Yamada Y, Yamashita J, Matsuda M, et al. Prognostic value of cyclin E and p53 expression in gastric carcinoma. Cancer. 1998;82:1238–43.
Lee KW, Kim HJ, Lee YS, Park HJ, Choi JW, Ha J, et al. Acteoside inhibits human promyelocytic HL-60 leukemia cell proliferation via inducing cell cycle arrest at G0/G1 phase and differentiation into monocyte. Carcinogenesis. 2007;28:1928–36.
Porter DC, Zhang N, Danes C, McGahren MJ, Harwell RM, Faruki S, et al. Tumor-specific proteolytic processing of cyclin E generates hyperactive lower-molecular-weight forms. Mol Cell Biol. 2001;21:6254–69.
Bales E, Mills L, Milam N, McGahren-Murray M, Bandyopadhyay D, Chen D, et al. The low molecular weight cyclin E isoforms augment angiogenesis and metastasis of human melanoma cells in vivo. Cancer Res. 2005;65:692–7.
Delk NA, Hunt KK, Keyomarsi K. Altered subcellular localization of tumor-specific cyclin E isoforms affects cyclin-dependent kinase 2 complex formation and proteasomal regulation. Cancer Res. 2009;69:2817–25.
Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science. 2001;294:173–7.
Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994;78:761–71.
Kloetzel PM, Ossendorp F. Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol. 2004;16:76–81.
Jiang YZ, Mavroudis D, Dermime S, Hensel N, Couriel D, Molldrem J, et al. Alloreactive CD4+T lymphocytes can exert cytotoxicity to chronic myeloid leukaemia cells processing and presenting exogenous antigen. Br J Haematol. 1996;93:606–12.
Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996;274:94–6.
Baumgarth N, Roederer M. A practical approach to multicolor flow cytometry for immunophenotyping. J Immunol Methods. 2000;243:77–97.
Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994;152:163–75.
Rammensee HG, Friede T, Stevanoviic S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41:178–228.
Caldon CE, Sergio CM, Sutherland RL, Musgrove EA. Differences in degradation lead to asynchronous expression of cyclin E1 and cyclin E2 in cancer cells. Cell Cycle. 2013;12:596–605.
Scuderi R, Palucka KA, Pokrovskaja K, Bjorkholm M, Wiman KG, Pisa P. Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood. 1996;87:3360–7.
Erlanson M, Portin C, Linderholm B, Lindh J, Roos G, Landberg G. Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications. Blood. 1998;92:770–7.
Wolowiec D, Benchaib M, Pernas P, Deviller P, Souchier C, Rimokh R, et al. Expression of cell cycle regulatory proteins in chronic lymphocytic leukemias. Comparison with non-Hodgkin's lymphomas and non-neoplastic lymphoid tissue. Leukemia. 1995;9:1382–8.
Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood. 2009;114:2733–43.
Park C, Choi YW, Hyun SK, Kwon HJ, Hwang HJ, Kim GY, et al. Induction of G1 arrest and apoptosis by schisandrin C isolated from Schizandra chinensis Baill in human leukemia U937 cells. Int J Mol Med. 2009;24:495–502.
Zang C, Liu H, Waechter M, Eucker J, Bertz J, Possinger K, et al. Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines. Cell Cycle. 2006;5:2237–43.
Bonifacino JS, Weissman AM. Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol. 1998;14:19–57.
Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol. 2005;23:975–1028.
Mittendorf EA, Alatrash G, Qiao N, Wu Y, Sukhumalchandra P, St John LS, et al. Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response. Cancer Res. 2012;72:3153–62.
Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y. Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis. 2001;60:433–41.
Caldon CE, Sergio CM, Burgess A, Deans AJ, Sutherland RL, Musgrove EA. Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1. Cell Cycle. 2013;12:606–17.
Gudas JM, Payton M, Thukral S, Chen E, Bass M, Robinson MO, et al. Cyclin E2, a novel G1 cyclin that binds Cdk2 and is aberrantly expressed in human cancers. Mol Cell Biol. 1999;19:612–22.
Zariwala M, Liu J, Xiong Y. Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins. Oncogene. 1998;17:2787–98.
Acknowledgements
This study was supported by research funding from NCI CA100632 (to JJM); NCI CA148600 (to JJM); Leukemia and Lymphoma Society 6030-12 (to JJM); P30 CA16672 (to KCD); Leukemia and Lymphoma Society 7262-08 (to JJM). The manuscript was edited by Department of Scientific Publications at M.D. Anderson Cancer Center.
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Authorship statement: HH, YK, KI, SL, KC, NQ, KCD, and PS performed experiments and analyzed data. GA, LSJ, and QM wrote the paper. JJM designed the research and wrote the paper.
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He, H., Kondo, Y., Ishiyama, K. et al. Two unique HLA-A*0201 restricted peptides derived from cyclin E as immunotherapeutic targets in leukemia. Leukemia 34, 1626–1636 (2020). https://doi.org/10.1038/s41375-019-0698-z
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DOI: https://doi.org/10.1038/s41375-019-0698-z