CD44 Is Selectively Required for the Homing and Engraftment of BCR-ABL-Expressing Leukemic Stem Cells.

Abstract

In chronic myeloid leukemia (CML) patients treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft can contribute to relapse of leukemia (Deisseroth et al., Blood 1994; 83:3068), but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Although the frequency of autografting in CML has decreased following the introduction of imatinib, most imatinib-responsive patients harbor residual BCR-ABL-expressing stem cells (Graham et al., Blood 2002; 99:319) and some will develop progressive leukemia. Autografting with cells harvested at the time of minimal residual disease could be an important salvage therapy, but methods to selectively block the engraftment of leukemic stem cells are needed. In this study, we show that CD44 expression is increased on murine BCR-ABL-expressing stem/progenitor cells and contributes to the ability of these cells to bind to Selectins. In a retroviral transduction/transplantation model of CML, BCR-ABL-transduced progenitors from CD44-deficient donors were defective in homing to recipient marrow, resulting in defective engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engrafted as efficiently as wild-type HSC. In addition, CD44 was not required for induction of acute B-lymphoblastic leukemia (B-ALL) by BCR-ABL, indicating that the engraftment requirement for CD44 is specific to leukemic cells initiating CML, not B-ALL. The requirement for donor CD44 was bypassed by direct intrafemoral injection of BCR-ABL-transduced CD44-deficient stem cells, or by co-expression of human CD44 with BCR-ABL. Treatment of BCR-ABL-transduced stem/progenitor cells from wild-type donors with antibody to CD44 attenuated the induction of CML-like leukemia in recipients. These results demonstrate a major role for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells, possibly through adhesive interactions with Selectins and/or hyaluronan in the recipient bone marrow niche. They further argue that BCR-ABL-transduced stem/progenitor cells depend to a greater extent on CD44 for engraftment than do normal HSC, and suggest that CD44 blockade may be beneficial in autologous transplantation in CML.