Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mechanisms controlling pathogenesis and survival of leukemic stem cells

Oncogene volume 23, pages 7178–7187 (2004)Cite this article

Abstract

Stem cells are an integral component of normal mammalian physiology and have been intensively studied in many systems. Intriguingly, substantial evidence indicates that stem cells also play an important role in the initiation and pathogenesis of at least some cancers. In particular, myeloid leukemias have been extensively characterized with regard to stem and progenitor cell involvement. Thus, as a focal point for both scientific and therapeutic endeavors, leukemic stem cells (LSC) represent a critical area of investigation. LSC appear to retain many characteristics of normal hematopoietic stem cells (HSC) as evidenced by a hierarchical developmental pattern, a mostly quiescent cell cycle profile, and an immunophenotype very similar to HSC. Consequently, defining unique properties of LSC remains a high priority in order to elucidate the molecular mechanisms driving stem cell transformation, and for developing therapeutic strategies that specifically target the LSC population. In this review, we discuss emerging concepts in the field and describe how various molecular and cellular characteristics of leukemia cells might be exploited as a means to preferentially ablate malignant stem cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Akashi K, Traver D, Miyamoto T and Weissman IL . (2000). Nature, 404, 193–197.

  • Baldwin AS . (1996). Annu. Rev. Immunol., 14, 649–683.

  • Birkenkamp KU, Geugien M, Schepers H, Westra J, Lemmink HH and Vellenga E . (2004). Leukemia, 18, 103–112.

  • Blair A, Hogge DE, Ailles LE, Lansdorp PM and Sutherland HJ . (1997). Blood, 89, 3104–3112.

  • Blair A, Hogge DE and Sutherland HJ . (1998). Blood, 92, 4325–4335.

  • Blair A and Sutherland HJ . (2000). Exp. Hematol., 28, 660–671.

  • Bonnet D and Dick JE . (1997). Nat. Med., 3, 730–737.

  • Brach MA, Kharbanda SM, Herrmann F and Kufe DW . (1992). Mol. Pharmacol., 41, 60–63.

  • Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J, Le Beau MM, Jacks TE and Shannon KM . (2004). Proc. Natl. Acad. Sci. USA, 101, 597–602.

  • Bruce WR and Gaag H . (1963). Nature, 199, 79–80.

  • Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H, Johnson L, Akashi K, Tuveson DA, Jacks T and Gilliland DG . (2004). J. Clin. Invest., 113, 528–538.

  • Charrad RS, Li Y, Delpech B, Balitrand N, Clay D, Jasmin C, Chomienne C and Smadja-Joffe F . (1999). Nat. Med., 5, 669–676.

  • Chaudhary PM and Roninson IB . (1991). Cell, 66, 85–94.

  • Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut JA and Olive D . (2000). Cancer Res., 60, 4403–4411.

  • Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML and Weissman IL . (2003). Genes Dev., 17, 3029–3035.

  • Cuenco GM and Ren R . (2001). Oncogene, 20, 8236–8248.

  • Dash A and Gilliland DG . (2001). Best. Pract. Res. Clin. Haematol., 14, 49–64.

  • Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, Li S, Van Etten RA, Borrow J, Housman D, Druker B and Gilliland DG . (2002). Proc. Natl. Acad. Sci. USA, 99, 7622–7627.

  • de Guzman CG, Warren AJ, Zhang Z, Gartland L, Erickson P, Drabkin H, Hiebert SW and Klug CA . (2002). Mol. Cell. Biol., 22, 5506–5517.

  • Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MA and Rafii S . (2001). Proc. Natl. Acad. Sci. USA, 98, 10857–10862.

  • Dick JE . (1996). Semin. Immunol., 8, 197–206.

  • Dosil M, Wang S and Lemischka IR . (1993). Mol. Cell. Biol., 13, 6572–6585.

  • Fialkow PJ, Gartler SM and Yoshida A . (1967). Proc. Natl. Acad. Sci. USA, 58, 1468–1471.

  • Fialkow PJ, Jacobson RJ and Papayannopoulou T . (1977). Am. J. Med., 63, 125–130.

  • Foulds L . (1969). Neoplastic Development. Academic Press: London.

    Google Scholar 

  • Foulds L . (1975). Neoplastic Development. Academic Press: London.

    Google Scholar 

  • Gilliland DG and Griffin JD . (2002). Blood, 100, 1532–1542.

  • Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD and Lander ES . (1999). Science, 286, 531–537.

  • Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L and Holyoake TL . (2002). Blood, 99, 319–325.

  • Guan Y, Gerhard B and Hogge DE . (2003). Blood, 101, 3142–3149.

  • Gutteridge JM and Quinlan GJ . (1985). Biochem. Pharmacol., 34, 4099–4103.

  • Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM and Jordan CT . (2001a). Blood, 98, 2301–2307.

  • Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ and Jordan CT . (2002). Proc. Natl. Acad. Sci. USA, 99, 16220–16225.

  • Guzman ML, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Phillips GL and Jordan CT . (2001b). Blood, 97, 2177–2179.

  • Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, Hallett W, Tsou HR, Upeslacis J, Shochat D, Mountain A, Flowers DA and Bernstein I . (2002). Bioconjug. Chem., 13, 47–58.

  • Harrison DE and Lerner CP . (1991). Blood, 78, 1237–1240.

  • Hazlehurst LA and Dalton WS . (2001). Cancer Metast. Rev., 20, 43–50.

  • Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J and Anderson KC . (2002). J. Biol. Chem., 277, 16639–16647.

  • Holyoake T, Jiang X, Eaves C and Eaves A . (1999). Blood, 94, 2056–2064.

  • Holyoake TL, Jiang X, Drummond MW, Eaves AC and Eaves CJ . (2002). Leukemia, 16, 549–558.

  • Hope KJ, Jin L and Dick JE . (2004). Nat. Immunol., 5, 738–743.

  • Jin L, Hope KJ, Dick JE and Smadja-Joffe F . (2003). Blood, 102, 622a.

  • Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, Meyerrose T, Rossi R, Grimes B, Rizzieri DA, Luger SM and Phillips GL . (2000). Leukemia, 14, 1777–1784.

  • Kamps MP and Baltimore D . (1993). Mol. Cell. Biol., 13, 351–357.

  • Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL and Gilliland DG . (2002). Blood, 99, 310–318.

  • Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T and Sauvageau G . (2001). EMBO J., 20, 350–361.

  • Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE . (1994). Nature, 367, 645–648.

  • Laurent G and Jaffrezou JP . (2001). Blood, 98, 913–924.

  • Lavau C, Du C, Thirman M and Zeleznik-Le N . (2000a). EMBO J., 19, 4655–4664.

  • Lavau C, Luo RT, Du C and Thirman MJ . (2000b). Proc. Natl. Acad. Sci. USA, 97, 10984–10989.

  • Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Kwong A, Komuves L, Buchberg AM and Largman C . (1999). Leukemia, 13, 1993–1999.

  • Lemischka IR . (1997). Stem Cells, 15 (Suppl 1), 63–68.

  • Lessard J and Sauvageau G . (2003). Nature, 423, 255–260.

  • Li S, Gillessen S, Tomasson MH, Dranoff G, Gilliland DG and Van Etten RA . (2001). Blood, 97, 1442–1450.

  • Li S, Ilaria Jr RL, Million RP, Daley GQ and Van Etten RA . (1999). J. Exp. Med., 189, 1399–1412.

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

  • Manz MG, Miyamoto T, Akashi K and Weissman IL . (2002). Proc. Natl. Acad. Sci. USA, 99, 11872–11877.

  • Mayo MW and Baldwin AS . (2000). Biochim. Biophys. Acta, 1470, M55–62.

  • Mayotte N, Roy D-C, Yao J, Kroon E and Sauvageau G . (2002). Blood, 100, 4177–4184.

  • Mulloy JC, Cammenga J, MacKenzie KL, Berguido FJ, Moore MA and Nimer SD. . (2002). Blood, 99, 15–23.

  • O'Dwyer ME and Druker BJ . (2000). Lancet Oncol., 1, 207–211.

  • Orlowski RZ and Baldwin Jr AS . (2002). Trends Mol. Med., 8, 385–389.

  • Park CH, Bergsagel DE and McCulloch EA . (1971). J. Natl. Cancer Inst., 46, 411–422.

  • Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ and Clarke MF . (2003). Nature, 423, 302–305.

  • Passegue E, Jamieson CH, Ailles LE and Weissman IL . (2003). Proc. Natl. Acad. Sci. USA, 100 (Suppl 1), 11842–11849.

  • Perry MC . (2001). The Chemotherapy Source Book 3rd edn. Lippincott Williams and Wilkins: Philadelphia.

    Google Scholar 

  • Ravandi F, Talpaz M, Kantarjian H and Estrov Z . (2002). Br. J. Haematol., 116, 57–77.

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

  • Romano MF, Lamberti A, Bisogni R, Tassone P, Pagnini D, Storti G, Del Vecchio L, Turco MC and Venuta S . (2000). Gene Ther., 7, 1234–1237.

  • Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ and Verheij M . (2003). Anticancer Drugs, 14, 167–173.

  • Schofield R . (1983). Biomed. Pharmacother., 37, 375–380.

  • Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE and McCubrey JA . (2004). Leukemia, 18, 189–218.

  • Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL and Radich JP . (2001). Blood, 97, 3589–3595.

  • Stucki A, Rivier AS, Gikic M, Monai N, Schapira M and Spertini O . (2001). Blood, 97, 2121–2129.

  • Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E, Adams J, Elliott P and Van Waes C . (2001). Clin. Cancer Res., 7, 1419–1428.

  • Tallman MS, Nabhan C, Feusner JH and Rowe JM . (2002). Blood, 99, 759–767.

  • Tergaonkar V, Pando M, Vafa O, Wahl G and Verma I . (2002). Cancer Cell, 1, 493–503.

  • Testa U, Riccioni R, Diverio D, Rossini A, Lo Coco F and Peschle C . (2004). Leukemia, 18, 219–226.

  • Thorsteinsdottir U, Kroon E, Jerome L, Blasi F and Sauvageau G . (2001). Mol. Cell. Biol., 21, 224–234.

  • Tomasson MH, Sternberg DW, Williams IR, Carroll M, Cain D, Aster JC, Ilaria Jr RL, Van Etten RA and Gilliland DG . (2000). J. Clin. Invest., 105, 423–432.

  • Tomasson MH, Williams IR, Li S, Kutok J, Cain D, Gillessen S, Dranoff G, Van Etten RA and Gilliland DG . (2001). Blood, 97, 1435–1441.

  • Turco MC, Romano MF, Petrella A, Bisogni R, Tassone P and Venuta S . (2004). Leukemia, 18, 11–17.

  • Van Etten RA . (2001). Curr. Opin. Hematol., 8, 224–230.

  • Wang CY, Cusack Jr JC, Liu R and Baldwin Jr AS . (1999). Nat. Med., 5, 412–417.

  • Wang JC, Lapidot T, Cashman JD, Doedens M, Addy L, Sutherland DR, Nayar R, Laraya P, Minden M, Keating A, Eaves AC, Eaves CJ and Dick JE . (1998). Blood, 91, 2406–2414.

  • Wierenga PK, Setroikromo R, Kamps G, Kampinga HH and Vellenga E . (2003). Exp. Hematol., 31, 421–427.

  • Wodinsky I, Swiniarski J and Kensler CJ . (1967). Cancer Chemother. Rep., 51, 415–421.

  • Xu Q, Simpson SE, Scialla TJ, Bagg A and Carroll M . (2003). Blood, 102, 972–980.

  • Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, Burel SA, Lagasse E, Weissman IL, Akashi K and Zhang DE . (2001). Proc. Natl. Acad. Sci. USA, 98, 10398–10403.

  • Zhao RC, Jiang Y and Verfaillie CM . (2001). Blood, 97, 2406–2412.

  • Zhao S, Konopleva M, Cabreira-Hansen M, Xie Z, Hu W, Milella M, Estrov Z, Mills GB and Andreeff M . (2004). Leukemia, 18, 267–275.

  • Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H and Sorrentino BP . (2001). Nat. Med., 7, 1028–1034.

  • Zhu Z, Hattori K, Zhang H, Jimenez X, Ludwig DL, Dias S, Kussie P, Koo H, Kim HJ, Lu D, Liu M, Tejada R, Friedrich M, Bohlen P, Witte L and Rafii S . (2003). Leukemia, 17, 604–611.

Download references

Acknowledgements

We gratefully acknowledge the assistance from Drs Mahesh Vaisnav and Fay Young in critical evaluation of this manuscript. The study was supported by grants from the NIH (R01-CA90446) and the American Cancer Society (RSG-03-096-01-LIB). CTJ is a scholar of the Leukemia and Lymphoma Society.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Rochester Medical Center, Box 703, 601 Elmwood Avenue, Rochester, 14642, NY, USA

    Craig T Jordan & Monica L Guzman

Authors
  1. Craig T Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica L Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig T Jordan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jordan, C., Guzman, M. Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23, 7178–7187 (2004). https://doi.org/10.1038/sj.onc.1207935

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207935

Keywords

This article is cited by

Search

Advanced search

Quick links