Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia.
Chronic myeloid leukemia (CML) has been studied intensively for many years; yet its treatment remains problematic and its biology remains elusive. In chronic phase, the leukemic clone appears to be maintained by a small number of BCR-ABL-positive hematopoietic stem cells that differentiate normally and amplify slowly. In contrast, as these cells enter the intermediate stages of lineage restriction, their progeny are selectively expanded and generate an enlarged pool of neoplastic progenitors. Recent analyses of purified subsets of primitive CML cells have provided a coherent explanation for this dichotomous behavior of BCR-ABL-positive stem and progenitor cells based on the discovery of an unusual autocrine IL-3/G-CSF mechanism activated in them. This only partially counteracts in vivosignals that maintain normal stem cells in a quiescent state but, when active in CML stem cells, promotes their differentiation in favor of their self-renewal. In more differentiated CML progenitors, the same mechanism has a more potent mitogenic effect which is then extinguished when the cells enter the terminal stages of differentiation. Thus, further expansion of the clone is limited until inevitably additional mutations are acquired that further distort or override the regulatory mechanisms still operative in the chronic phase.
Holyoake
T L
TL
Departments of Medicine and Hematology, Glasgow Royal Infirmary, Glasgow, UK.
Jiang
X
X
Drummond
M W
MW
Eaves
A C
AC
Eaves
C J
CJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D002455:Cell Division; D002869:Chromosome Aberrations; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008875:Middle Aged; D016615:Telomere / Q000502:physiology
D015703:Antigens, CD; D016044:Fusion Proteins, bcr-abl