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Targeting of CD44 eradicates human acute myeloid leukemic stem cells

Abstract

The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell–supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.

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Figure 1: In vivo activation of CD44 by administration of H90 inhibits AML cell growth in NOD-SCID mice.
Figure 2: Differentiation of immature blasts induced by H90-mediated CD44 activation in vitro and in vivo.
Figure 3: Selective inhibitory effect of H90 on SL-IC.
Figure 4: Inhibition of AML cell homing and transendothelial migration by CD44 ligation.
Figure 5: Alteration of migratory behavior of primitive AML cells due to H90 treatment.

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References

  1. Wang, J.C. & Dick, J.E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Hope, K., Jin, L. & Dick, J.E. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat. Immunol. 5, 738–743 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Guan, Y. & Hogge, D.E. Proliferative status of primitive hematopoietic progenitors from patients with acute myelogenous leukemia (AML). Leukemia 14, 2135–2141 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Guzman, M.L. et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301–2307 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Tallman, M.S. New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. Hematology Am. Soc. Hematol. Educ. Program 2005, 143–150 (2005).

    Article  Google Scholar 

  8. Wilson, A. & Trumpp, A. Bone-marrow haematopoietic-stem-cell niches. Nat. Rev. Immunol. 6, 93–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Nilsson, S.K. et al. Hyaluronan is synthesized by primitive hemopoietic cells, participates in their lodgment at the endosteum following transplantation, and is involved in the regulation of their proliferation and differentiation in vitro. Blood 101, 856–862 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Calvi, L.M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Cancelas, J.A. & Williams, D.A. Stem cell mobilization by β2-agonists. Nat. Med. 12, 278–279 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Lapidot, T., Dar, A. & Kollet, O. How do stem cells find their way home? Blood 106, 1901–1910 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Kortlepel, K., Bendall, L.J. & Gottlieb, D.J. Human acute myeloid leukaemia cells express adhesion proteins and bind to bone marrow fibroblast monolayers and extracellular matrix proteins. Leukemia 7, 1174–1179 (1993).

    CAS  PubMed  Google Scholar 

  15. Reuss-Borst, M.A., Buhring, H.J., Klein, G. & Muller, C.A. Adhesion molecules on CD34+ hematopoietic cells in normal human bone marrow and leukemia. Ann. Hematol. 65, 169–174 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Liesveld, J.L. et al. Adhesive interactions of normal and leukemic human CD34+ myeloid progenitors: role of marrow stromal, fibroblast, and cytomatrix components. Exp. Hematol. 19, 63–70 (1991).

    CAS  PubMed  Google Scholar 

  17. Tavor, S. et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res. 64, 2817–2824 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Till, J.E. & McCulloch, E.A. Hemopoietic stem cell differentiation. Biochim. Biophys. Acta 605, 431–459 (1980).

    CAS  PubMed  Google Scholar 

  19. Ponta, H., Sherman, L. & Herrlich, P.A. CD44: from adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 4, 33–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Bendall, L.J., Bradstock, K.F. & Gottlieb, D.J. Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD34+ cells. Leukemia 14, 1239–1246 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Legras, S. et al. A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood 91, 3401–3413 (1998).

    CAS  PubMed  Google Scholar 

  22. Avigdor, A. et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 103, 2981–2989 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Turley, E.A., Noble, P.W. & Bourguignon, L.Y. Signaling properties of hyaluronan receptors. J. Biol. Chem. 277, 4589–4592 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Charrad, R.S. et al. Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat. Med. 5, 669–676 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Charrad, R.S. et al. Effects of anti-CD44 monoclonal antibodies on differentiation and apoptosis of human myeloid leukemia cell lines. Blood 99, 290–299 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Gadhoum, Z. et al. CD44: a new means to inhibit acute myeloid leukemia cell proliferation via P27Kip1. Blood 103, 1059–1068 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Mohle, R. et al. The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell–derived factor-1. Blood 91, 4523–4530 (1998).

    CAS  PubMed  Google Scholar 

  28. Mazurier, F., Doedens, M., Gan, O.I. & Dick, J.E. Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nat. Med. 9, 959–963 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Mazurier, F., Gan, O., McKenzie, J., Doedens, M. & Dick, J. Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood 103, 545–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Madlambayan, G.J. et al. Dynamic changes in cellular and microenvironmental composition can be controlled to elicit in vitro human hematopoietic stem cell expansion. Exp. Hematol. 33, 1229–1239 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Kim, C.F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Singh, S. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5281–5288 (2003).

    Google Scholar 

  34. Al-Hajj, M., Wicha, M., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liotta, L.A. & Kohn, E.C. The microenvironment of the tumour-host interface. Nature 411, 375–379 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Woerner, S.M. et al. Expression of CD44 splice variants in normal, dysplastic, and neoplastic cervical epithelium. Clin. Cancer Res. 1, 1125–1132 (1995).

    CAS  PubMed  Google Scholar 

  37. Jo, D.Y., Rafii, S., Hamada, T. & Moore, M.A. Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1. J. Clin. Invest. 105, 101–111 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge M. Minden for providing AML samples, and members of the Dick laboratory and T. Lapidot for critical comments on the manuscript. This work was supported by a Canadian Institutes of Health Research studentship (K.J.H.) and fellowship (L.J.), grants from the Leukemia and Lymphoma Society, Fondation de France, Association pour la Recherche sur le Cancer (F.S.-J.) and grants from the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the Terry Fox Foundation, Canadian Institutes of Health Research, Ontario Cancer Research Network, Genome Canada through the Ontario Genomics Institute, and a Canada Research Chair (J.E.D.). Research support (F.S.-J.) and H90 mAb production were provided by MAT Biopharma.

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Authors and Affiliations

Authors

Contributions

The study was designed by L.J., K.J.H., F.S.-J. and J.E.D.; experiments were performed by L.J., K.J.H. and Q.Z.; and all authors contributed to writing the paper.

Corresponding author

Correspondence to John E Dick.

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Competing interests

F.S.-J. received some research support from MAT BioPharma, which also provided the purified monoclonal antibody used in the the study.

Supplementary information

Supplementary Fig. 1

Distinct characteristics of human cells in NOD-SCID mice transplanted with human AML or normal cord blood cells. (PDF 314 kb)

Supplementary Fig. 2

Increase in differentiated granulocytic cells induced by CD44 ligation in vivo. (PDF 106 kb)

Supplementary Fig. 3

Selective inhibitory effect of H90 on SL-ICs. (PDF 102 kb)

Supplementary Fig. 4

Effect of H90 on adhesion of primitive AML and normal BM cells to hyaluronan. (PDF 109 kb)

Supplementary Table 1

In vitro differentiation. (PDF 53 kb)

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Jin, L., Hope, K., Zhai, Q. et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12, 1167–1174 (2006). https://doi.org/10.1038/nm1483

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