PMID- 9531612
OWN - NLM
STAT- MEDLINE
DCOM- 19980512
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 91
IP  - 8
DP  - 1998 Apr 15
TI  - Role of p53 in hematopoietic recovery after cytotoxic treatment.
PG  - 2998-3006
AB  - 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+ CD34(low/-)) did not depend on p53, the percentage of 
      multipotential HSCs and committed progenitors (Lin- Sca-1(+) c-Kit+ CD34(high/+)) 
      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.
FAU - Wlodarski, P
AU  - Wlodarski P
AD  - Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas 
      Jefferson University, Philadelphia, PA, USA.
FAU - Wasik, M
AU  - Wasik M
FAU - Ratajczak, M Z
AU  - Ratajczak MZ
FAU - Sevignani, C
AU  - Sevignani C
FAU - Hoser, G
AU  - Hoser G
FAU - Kawiak, J
AU  - Kawiak J
FAU - Gewirtz, A M
AU  - Gewirtz AM
FAU - Calabretta, B
AU  - Calabretta B
FAU - Skorski, T
AU  - Skorski T
LA  - eng
GR  - R29 CA70815/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antimetabolites)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Animals
MH  - Antimetabolites/*toxicity
MH  - Apoptosis/drug effects/*genetics
MH  - Fluorouracil/*toxicity
MH  - Gene Expression Regulation/drug effects
MH  - Genes, Tumor Suppressor/genetics
MH  - Hematopoiesis/drug effects/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Tumor Suppressor Protein p53/*genetics
EDAT- 1998/05/16 00:00
MHDA- 1998/05/16 00:01
CRDT- 1998/05/16 00:00
PHST- 1998/05/16 00:00 [pubmed]
PHST- 1998/05/16 00:01 [medline]
PHST- 1998/05/16 00:00 [entrez]
AID - S0006-4971(20)55309-3 [pii]
PST - ppublish
SO  - Blood. 1998 Apr 15;91(8):2998-3006.