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Role of p53 in Hematopoietic Recovery After Cytotoxic Treatment
Pawel Wlodarski,
Mariusz Wasik,
Mariusz Z. Ratajczak,
Cinzia Sevignani,
Grazyna Hoser,
Jerzy Kawiak,
Alan M. Gewirtz,
Bruno Calabretta, and
Thomas Skorski
From the Department of Microbiology and Immunology, Kimmel Cancer
Institute, Thomas Jefferson University, Philadelphia, PA; the
Department of Pathology and Laboratory Medicine, University of
Pennsylvania, Philadelphia, PA; and the Medical Center of Postgraduate
Education, Warsaw, Poland.
Prompt reconstitution of hematopoiesis after cytoreductive therapy
is essential for patient recovery and may have a positive impact on
long-term prognosis. We examined the role of the p53 tumor suppressor
gene in hematopoietic recovery in vivo after treatment with the
cytotoxic drug 5-fluorouracil (5-FU). We used p53 knock-out
(p53 /) and wild-type (p53+/+) mice injected with 5-FU as the
experimental model. Analysis of the repopulation ability and clonogenic
activity of hematopoietic stem cells (HSCs) and their lineage-committed
descendants showed a greater number of HSCs responsible for
reconstitution of lethally irradiated recipients in p53/ bone
marrow cells (BMCs) recovering after 5-FU treatment than in the
corresponding p53+/+ BMCs. In post-5-FU recovering BMCs, the
percentage of HSC-enriched Lin Sca-1+
c-Kit+ cells was about threefold higher in p53/
than in p53+/+ cells. Although the percentage of the most primitive
HSCs (Lin Sca-1+ c-Kit+
CD34low/) did not depend on p53, the percentage of
multipotential HSCs and committed progenitors (Lin
Sca-1+ c-Kit+ CD34high/+) was
almost fourfold higher in post-5-FU recovering p53/ BMCs than in
their p53+/+ counterparts. The pool of HSCs from 5-FU-treated p53/ BMCs was exhausted more slowly than that from the p53+/+ population as shown in vivo using pre-spleen colony-forming unit (CFU-S) assay and in vitro using long-term
culture-initiating cells (LTC-ICs) and methylcellulose replating
assays. Clonogenic activity of various lineage-specific descendants was
significantly higher in post-5-FU regenerating p53/ BMCs than in
p53+/+ BMCs, probably because of their increased sensitivity to
growth factors. Despite all these changes and the dramatic difference
in sensitivity of p53/ and p53+/+ BMCs to 5-FU-induced
apoptosis, lineage commitment and differentiation of hematopoietic
progenitors appeared to be independent of p53 status. These studies
suggest that suppression of p53 function facilitates hematopoietic
reconstitution after cytoreductive therapy by: (1) delaying the
exhaustion of the most primitive HSC pool, (2) stimulating the
production of multipotential HSCs, (3) increasing the sensitivity of
hematopoietic cells to growth factors, and (4) decreasing the
sensitivity to apoptosis.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2998-3006
© 1998 by The American Society of Hematology.
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