Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3

It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G(0)) leukemic (Philadelphia chromosome-positive and BCR-ABL-positive [BCR-ABL(+)]) CD34(+) cells. In the study described here, most such cells expressed a primitive phenotype (CD38(-), CD45RA(-), CD71(-), and HLA-DRlo) and cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do cultures of initially cycling CD34(+) leukemic cells. Initially quiescent leukemic cells expressing BCR-ABL proliferated in single-cell cultures in the absence of added growth factors, thereby demonstrating their ability to spontaneously exit G(0) and enter a continuously cycling state, Interestingly, on isolation, few of these quiescent BCR-ABL(+) cells contained either interleukin-3 (IL-3) or granulocyte colony-stimulating factor (G-CSF) transcripts, whereas both were present in most cycling BCR-ABL(+) CD34(+) cells. However, after 4 days of culture in the absence of added growth factors and in association with their entry into the cell cycle (as indicated by up-regulation of Ki-67 and cdc25 transcripts), IL-3 transcripts became detectable. These findings show that entry of leukemic (BCR-ABL-expressing) progenitors into a quiescent (G(0)) state in vivo is highest among the most primitive leukemic cell populations, associated with a down-regulation of IL-3 and G-CSF gene expression, and spontaneously reversible in association with up-regulation of IL-3 expression, These results highlight the potential physiologic relevance of quiescent CML progenitors, even in treated patients, In whom these cells would be predicted to have a proliferative advantage over their quiescent normal counterparts when cytokine concentrations are low. (C) 2001 by The American Society of Hematology.