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)

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Abstract

It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G<sub>0</sub>) leukemic (Philadelphia chromosome-positive and <i>BCR-ABL</i>-positive [<i>BCR-ABL<sup>+</sup></i>]) CD34<sup>+</sup> cells. In the study described here, most such cells expressed a primitive phenotype (CD38<sup>-</sup>, CD45RA<sup>-</sup>, CD71<sup>-</sup>, and HLA-DR<sup>lo</sup>) and cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do cultures of initially cycling CD34<sup>+</sup> 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 G<sub>0</sub> and enter a continuously cycling state, Interestingly, on isolation, few of these quiescent <i>BCR-ABL<sup>+</sup></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<sup>+</sup></i> CD34<sup>+</sup> 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 (G<sub>0</sub>) 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 > Institute of Cancer Sciences
Journal Name:Blood
ISSN:0006-4971

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