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Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells

Abstract

In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse1, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1–transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1–transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL–expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML.

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Figure 1: CD44 is increased on BCR-ABL–expressing CML-initiating cells and required for homing and engraftment.
Figure 2: Donor CD44 is not required for engraftment of B-ALL–initiating cells.
Figure 3: Engraftment defect of BCR-ABL1–transduced Cd44−/− progenitors is rescued by direct intrafemoral injection or by coexpression of human CD44s.
Figure 4: CD44-specific antibody treatment prolongs survival of recipients of BCR-ABL1–transduced progenitors.

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Acknowledgements

We thank J.E. Dick for advice about intrafemoral injections and I. Mazo for assistance with flow cytometry. This work was supported by the US National Institutes of Health (grant HL56949 to U.H.v.A. and R.A.V.).

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Correspondence to Richard A Van Etten.

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Supplementary information

Supplementary Fig. 1

Serial flow cytometric analysis of peripheral blood from a representative WT recipient of BCR-ABL1–transduced Cd44−/− BM that did not develop fatal CML-like leukemia. (PDF 86 kb)

Supplementary Fig. 2

Flow cytometric analysis of primary B-lymphoid progenitors from WT or Cd44−/− (CD44 KO) donors, transformed in vitro (Roumiantsev et al., Blood 97, 4–13 (2001)) with retrovirus co-expressing BCR-ABL and either GFP (B-A + GFP) or human CD44s (B-A + huCD44). (PDF 88 kb)

Supplementary Table 1

Quantitation of engrafting proviral clones in leukemic cohorts. (PDF 37 kb)

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Krause, D., Lazarides, K., von Andrian, U. et al. Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells. Nat Med 12, 1175–1180 (2006). https://doi.org/10.1038/nm1489

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