Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib.

摘要: Drug resistance is a growing area of concern. It has been shown that small, residual pool leukemic CD34+ progenitor cells can survive in the marrow microenvironment chronic myeloid leukemia (CML) patients after years kinase inhibitor treatment. Bone (BM) stroma implicated long-term survival cells, and contributes to expansion proliferation both transformed normal hematopoietic cells. Mechanistically, we found CML expressed CXCR4, plerixafor diminished BCR-ABL-positive cell migration reduced adhesion these extra cellular-matrix components BM stromal vitro. Moreover, decreased drug induced by co-culture with Using functional mouse model progressive disease, demonstrated ability CXCR4 inhibitor, plerixafor, mobilize vivo, such plerixafor-nilotinib combination burden mice significantly below baseline level suppression exhibited moderate-to-high dose nilotinib as single agent. These results support idea using inhibition conjunction targeted tyrosine override suppress or eradicate disease.