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

Holyoake, T.L., Jiang, X.Y., Jorgensen, H.G. , Graham, S., Alcorn, M.J., Laird, C., Eaves, A.C. and Eaves, C.J. (2001) 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. Blood, 97(3), pp. 720-728. (doi: 10.1182/blood.V97.3.720)

Abstract

It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G₀) leukemic (Philadelphia chromosome-positive and <i>BCR-ABL</i>-positive [<i>BCR-ABL⁺</i>]) CD34⁺ cells. In the study described here, most such cells expressed a primitive phenotype (CD38^-, CD45RA^-, CD71^-, and HLA-DR^lo) 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 <i>BCR-ABL</i> proliferated in single-cell cultures in the absence of added growth factors, thereby demonstrating their ability to spontaneously exit G₀ and enter a continuously cycling state, Interestingly, on isolation, few of these quiescent <i>BCR-ABL⁺</i> cells contained either interleukin-3 (IL-3) or granulocyte colony-stimulating factor (G-CSF) transcripts, whereas both were present in most cycling <i>BCR-ABL⁺</i> 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 (<i>BCR-ABL</i>-expressing) progenitors into a quiescent (G₀) 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa and Jorgensen, Dr Heather
• Authors: Holyoake, T.L., Jiang, X.Y., Jorgensen, H.G., Graham, S., Alcorn, M.J., Laird, C., Eaves, A.C., and Eaves, C.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• ISSN: 0006-4971