HYPOXIA SUPPRESSES BCR/ABL AND SELECTS IMATINIB-INSENSITIVE PROGENITORS WITHIN CLONAL CML POPULATIONS.

We previously showed that resistance to severe hypoxia defines hierarchycal levels of progenitors within normal hematopoietic populations and enhances the maintenance of stem cells. This study addressed the questions whether (a) cells endowed with different levels of sensitivity to hypoxia were identifiable within clonal chronic myeloid leukemia (CML) cell populations, and (b) hypoxia-resistant cells were related to those responsible for CML resistance to the treatment with Imatinibmesylate. CML cell lines were found to comprise hypoxia-sensitive colony-forming cells as well as hypoxia-resistant progenitors of the shortterm repopulating type. The latter were completely Imatinib-insensitive and lacked BCR/Abl protein, but not mRNA, expression. This is the first study directly linking hypoxia-resistance of CML progenitors to BCR/Abl-independence and Imatinib-insensitivity and pointing to a metabolic peculiarity which is relevant to the maintenance of cancer stem cells in solid tumors.