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Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells

Oncogene volume 30, pages 1009–1019 (2011)Cite this article

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Abstract

Accumulating evidence indicates that many human cancers are organized as a cellular hierarchy initiated and maintained by self-renewing cancer stem cells. This cancer stem cell model has been most conclusively established for human acute myeloid leukemia (AML), although controversies still exist regarding the identity of human AML stem cells (leukemia stem cell (LSC)). A major implication of this model is that, in order to eradicate the cancer and cure the patient, the cancer stem cells must be eliminated. Monoclonal antibodies have emerged as effective targeted therapies for the treatment of a number of human malignancies and, given their target antigen specificity and generally minimal toxicity, are well positioned as cancer stem cell-targeting therapies. One strategy for the development of monoclonal antibodies targeting human AML stem cells involves first identifying cell surface antigens preferentially expressed on AML LSC compared with normal hematopoietic stem cells. In recent years, a number of such antigens have been identified, including CD123, CD44, CLL-1, CD96, CD47, CD32, and CD25. Moreover, monoclonal antibodies targeting CD44, CD123, and CD47 have demonstrated efficacy against AML LSC in xenotransplantation models. Hopefully, these antibodies will ultimately prove to be effective in the treatment of human AML.

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References

  • Adams GP, Weiner LM . (2005). Monoclonal antibody therapy of cancer. Nat Biotechnol 23: 1147–1157.

    Article  CAS  PubMed  Google Scholar 

  • Ailles LE, Gerhard B, Hogge DE . (1997). Detection and characterization of primitive malignant and normal progenitors in patients with acute myelogenous leukemia using long-term coculture with supportive feeder layers and cytokines. Blood 90: 2555–2564.

    CAS  PubMed  Google Scholar 

  • Ailles LE, Gerhard B, Kawagoe H, Hogge DE . (1999). Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. Blood 94: 1761–1772.

    CAS  PubMed  Google Scholar 

  • Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA et al. (2004). C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 64: 8443–8450.

    Article  CAS  PubMed  Google Scholar 

  • Barclay AN, Brown MH . (2006). The SIRP family of receptors and immune regulation. Nat Rev Immunol 6: 457–464.

    Article  CAS  PubMed  Google Scholar 

  • Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B . (1992). Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci USA 89: 2804–2808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. (1976). Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33: 451–458.

    Article  CAS  PubMed  Google Scholar 

  • Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ . (1997). Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89: 3104–3112.

    CAS  PubMed  Google Scholar 

  • Blair A, Hogge DE, Sutherland HJ . (1998). Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR. Blood 92: 4325–4335.

    CAS  PubMed  Google Scholar 

  • Blazar BR, Lindberg FP, Ingulli E, Panoskaltsis-Mortari A, Oldenborg PA, Iizuka K et al. (2001). CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells. J Exp Med 194: 541–549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonnet D, Dick JE . (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737.

    Article  CAS  PubMed  Google Scholar 

  • Brown EJ, Frazier WA . (2001). Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 11: 130–135.

    Article  CAS  PubMed  Google Scholar 

  • Burnett AK, Mohite U . (2006). Treatment of older patients with acute myeloid leukemia—new agents. Semin Hematol 43: 96–106.

    Article  CAS  PubMed  Google Scholar 

  • Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S et al. (2010). Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142: 699–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charrad RS, Li Y, Delpech B, Balitrand N, Clay D, Jasmin C et al. (1999). Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat Med 5: 669–676.

    Article  CAS  PubMed  Google Scholar 

  • Cheson BD, Leonard JP . (2008). Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N Engl J Med 359: 613–626.

    Article  CAS  PubMed  Google Scholar 

  • Craig W, Kay R, Cutler RL, Lansdorp PM . (1993). Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med 177: 1331–1342.

    Article  CAS  PubMed  Google Scholar 

  • Dalerba P, Cho RW, Clarke MF . (2007). Cancer stem cells: models and concepts. Annu Rev Med 58: 267–284.

    Article  CAS  PubMed  Google Scholar 

  • Dick JE . (2008). Stem cell concepts renew cancer research. Blood 112: 4793–4807.

    Article  CAS  PubMed  Google Scholar 

  • Estey E, Dohner H . (2006). Acute myeloid leukaemia. Lancet 368: 1894–1907.

    Article  PubMed  Google Scholar 

  • Finn OJ . (2008). Cancer immunology. N Engl J Med 358: 2704–2715.

    Article  CAS  PubMed  Google Scholar 

  • Florian S, Sonneck K, Hauswirth AW, Krauth MT, Schernthaner GH, Sperr WR et al. (2006). Detection of molecular targets on the surface of CD34+/CD38—stem cells in various myeloid malignancies. Leuk Lymphoma 47: 207–222.

    Article  CAS  PubMed  Google Scholar 

  • Gilliland DG, Griffin JD . (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood 100: 1532–1542.

    Article  CAS  PubMed  Google Scholar 

  • Gilliland DG, Jordan CT, Felix CA . (2004). The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program, 80–97.

    Article  Google Scholar 

  • Gramatzki M, Ludwig WD, Burger R, Moos P, Rohwer P, Grunert C et al. (1998). Antibodies TC-12 (‘unique’) and TH-111 (CD96) characterize T-cell acute lymphoblastic leukemia and a subgroup of acute myeloid leukemia. Exp Hematol 26: 1209–1214.

    CAS  PubMed  Google Scholar 

  • Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M et al. (2007). CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA 104: 11008–11013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G et al. (2005). Development of functional human blood and immune systems in NOD/SCID/IL2 rec. Blood 106: 1565–1573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. (2007). Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25: 1315–1321.

    Article  CAS  PubMed  Google Scholar 

  • Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138: 271–285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jawad M, Seedhouse C, Mony U, Grundy M, Russell NH, Pallis M . (2010). Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia. Leukemia 24: 74–80.

    Article  CAS  PubMed  Google Scholar 

  • Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . (2006). Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12: 1167–1174.

    Article  PubMed  Google Scholar 

  • Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L et al. (2009). Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5: 31–42.

    Article  CAS  PubMed  Google Scholar 

  • Jordan CT, Guzman ML, Noble M . (2006). Cancer stem cells. N Engl J Med 355: 1253–1261.

    Article  CAS  PubMed  Google Scholar 

  • Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL et al. (2000). The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14: 1777–1784.

    Article  CAS  PubMed  Google Scholar 

  • Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A . (2007). Tumor growth need not be driven by rare cancer stem cells. Science 317: 337.

    Article  CAS  PubMed  Google Scholar 

  • Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648.

    Article  CAS  PubMed  Google Scholar 

  • Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L et al. (2005). Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 106: 673–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowenberg B, Downing JR, Burnett A . (1999). Acute myeloid leukemia. N Engl J Med 341: 1051–1062.

    Article  CAS  PubMed  Google Scholar 

  • Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD et al. (2009). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138: 286–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majeti R, Park CY, Weissman IL . (2007). Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1: 635–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyamoto T, Weissman IL, Akashi K . (2000). AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA 97: 7521–7526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murray L, Chen B, Galy A, Chen S, Tushinski R, Uchida N et al. (1995). Enrichment of human hematopoietic stem cell activity in the CD34+Thy-1+Lin- subpopulation from mobilized peripheral blood. Blood 85: 368–378.

    CAS  PubMed  Google Scholar 

  • Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y et al. (2005). Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. J Immunol 174: 2004–2011.

    Article  CAS  PubMed  Google Scholar 

  • Oldenborg PA, Gresham HD, Lindberg FP . (2001). CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis. J Exp Med 193: 855–862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP . (2000). Role of CD47 as a marker of self on red blood cells. Science 288: 2051–2054.

    Article  CAS  PubMed  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . (2008). Efficient tumour formation by single human melanoma cells. Nature 456: 593–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

    Article  CAS  PubMed  Google Scholar 

  • Roberts AW, He S, Bradstock KF, Hertzberg MS, Durrant STS, Ritchie D et al. (2008). A phase 1 and correlative biological study of CSL360 (anti-CD123 mAb) in AML. Blood 112: 2956a.

    Article  Google Scholar 

  • Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S et al. (2010). Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med 2: 17ra19.

    Article  Google Scholar 

  • Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S et al. (2005). Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174: 6477–6489.

    Article  CAS  PubMed  Google Scholar 

  • Shultz LD, Ishikawa F, Greiner DL . (2007). Humanized mice in translational biomedical research. Nat Rev Immunol 7: 118–130.

    Article  CAS  PubMed  Google Scholar 

  • Stasi R, Evangelista ML, Buccisano F, Venditti A, Amadori S . (2008). Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer Treat Rev 34: 49–60.

    Article  CAS  PubMed  Google Scholar 

  • Subramanian S, Parthasarathy R, Sen S, Boder ET, Discher DE . (2006). Species- and cell type-specific interactions between CD47 and human SIRPalpha. Blood 107: 2548–2556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI et al. (2007). Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 8: 1313–1323.

    Article  CAS  PubMed  Google Scholar 

  • Tan BT, Park CY, Ailles LE, Weissman IL . (2006). The cancer stem cell hypothesis: a work in progress. Lab Invest 86: 1203–1207.

    Article  CAS  PubMed  Google Scholar 

  • Taussig DC, Miraki-Moud F, Anjos-Afonso F, Pearce DJ, Allen K, Ridler C et al. (2008). Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 112: 568–575.

    Article  CAS  PubMed  Google Scholar 

  • Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G et al. (2005). Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106: 4086–4092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T et al. (2010). Leukemia initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34- fraction. Blood 115: 1976–1984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terwijn M, Feller N, van Rhenen A, Kelder A, Westra G, Zweegman S et al. (2009). Interleukin-2 receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level of residual disease in AML. Eur J Cancer 45: 1692–1699.

    Article  CAS  PubMed  Google Scholar 

  • Testa U, Riccioni R, Diverio D, Rossini A, Lo Coco F, Peschle C . (2004). Interleukin-3 receptor in acute leukemia. Leukemia 18: 219–226.

    Article  CAS  PubMed  Google Scholar 

  • van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. (2005). High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 11: 6520–6527.

    Article  CAS  PubMed  Google Scholar 

  • van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B et al. (2007). The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110: 2659–2666.

    Article  CAS  PubMed  Google Scholar 

  • Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. (2009). The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114: 937–951.

    Article  CAS  PubMed  Google Scholar 

  • Wang PL, O'Farrell S, Clayberger C, Krensky AM . (1992). Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily. J Immunol 148: 2600–2608.

    CAS  PubMed  Google Scholar 

  • Yalcintepe L, Frankel AE, Hogge DE . (2006). Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice. Blood 108: 3530–3537.

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Singh S, Pardoux C, Zhao J, Hsi ED, Abo A et al. (2010). Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica 95: 71–78.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to acknowledge Mark Chao and Max Jan for critical review of the manuscript and Irv Weissman for support and mentorship. This work was supported in part by a grant from the American Association for Cancer Research. RM holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. RM has filed the US Patent Application Serial No. 12/321,215 entitled ‘Methods For Manipulating Phagocytosis Mediated by CD47’.

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  1. Division of Hematology, Department of Internal Medicine, Cancer Center, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA, USA

    R Majeti

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Majeti, R. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene 30, 1009–1019 (2011). https://doi.org/10.1038/onc.2010.511

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