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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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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

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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