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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2604-2610
HEMATOPOIESIS
The influence of INK4 proteins on growth and self-renewal
kinetics of hematopoietic progenitor cells
John L. Lewis,
Wimol Chinswangwatanakul,
Bo Zheng,
Stephen B. Marley,
Dao X. Nguyen,
Nicholas C. P. Cross,
Lolita Banerji,
Janet Glassford,
N. Shaun B. Thomas,
John M. Goldman,
Eric W.-F. Lam, and
Myrtle Y. Gordon
From the LRF Centre for Adult Leukaemia, Department of
Haematology, Imperial College School of Medicine, Hammersmith Campus;
the Ludwig Institute for Cancer Research and Section of Virology and
Cell Biology, Imperial College School of Medicine, St Mary's Campus;
and the Department of Haematological Medicine, Guy's, King's and St
Thomas' School of Medicine and Dentistry, King's Denmark Hill Campus,
London, United Kingdom.
This study investigated the influence of expression of proteins of
the INK4 family, particularly p16, on the growth and self-renewal kinetics of hematopoietic cells. First, retrovirus-mediated gene transfer (RMGT) was used to restore p16INK4a
expression in the p16INK4a-deficient lymphoid and myeloid
cell lines BV173 and K562, and it was confirmed that this inhibited
their growth. Second, to sequester p16INK4a and related
INK4 proteins, cyclin-dependent kinase 4 (CDK4) was retrovirally
transduced into normal human CD34+ bone marrow cells and
then cultured in myeloid colony-forming cell (CFC) assays. The growth
of CDK4-transduced colonies was more rapid; the cell-doubling time was
reduced; and, upon replating, the colonies produced greater yields of
secondary colonies than mock-untransduced controls. Third, colony
formation was compared by marrow cells from
p16INK4a / mice and wild-type mice. The results
from p16INK4a/ marrow were similar to those
from CDK4-transduced human CFCs, in terms of growth rate and replating
ability, and were partially reversed by RMGT of
p16INK4a. Lines of immature granulocytic cells
were raised from 15 individual colonies grown from the marrow of
p16INK4a/ mice. These had a high
colony-forming ability (15%) and replating efficiency (96.7%).
The p16INK4a/ cell lines readily
became growth factor-independent upon cytokine deprivation. Taken
together, these results demonstrate that loss of INK4 proteins, in
particular p16INK4a, increases the growth rate of myeloid
colonies in vitro and, more importantly, confers an increased ability
for clonal expansion on hematopoietic progenitor cells.
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