Role of p53 in hematopoietic recovery after cytotoxic treatment
Role of p53 in hematopoietic recovery after cytotoxic treatment
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DOI：
10.1182/blood.v91.8.2998.2998_2998_3006
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发表时间：
1998-04-15
期刊：
影响因子：
20.3
通讯作者：
Skorski, T
中科院分区：
文献类型：
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作者：
Wlodarski, P;Wasik, M;Skorski, T
细胞减灭术后迅速重建造血系统对患者的康复至关重要，并可能对患者的长期预后产生积极影响。我们检测了细胞毒性药物5-氟尿嘧啶(5-FU)治疗后，p53肿瘤抑制基因在体内造血恢复中的作用。我们用p53基因敲除(P53-/-)和野生型(P53+/+)小鼠注射5-FU作为实验模型。对造血干细胞(HSCs)及其血统承诺的后代的再繁殖能力和克隆活性的分析表明，在经5-FU治疗后恢复的P53-/-骨髓细胞(BMCs)中，负责重建致死照射受者的HSCs的数量多于相应的P53+/+BMCs。在5-FU复苏的骨髓细胞中，P53-/-细胞中HSC富集率约为P53+/+细胞的3倍。尽管最原始的HSCs(LIN(-)Sca-1(+)c-Kit(+)CD34(low/-))的比例不依赖于P53，但在5-FU恢复P53-/-BMC后，多潜能HSCs和承诺祖细胞(LIN(-)Sca-1(+)c-Kit(+)CD34(HIGH/+)的比例几乎是P53+/+BMCs的4倍。经5-FU处理的P53-/-BMCs的HSCs在体内的脾前集落形成单位(CPU-S)试验和体外长期培养启动细胞(LTC-ICs)和甲基纤维素复制试验中显示出比来自P53+/+的BMCs更慢的耗竭。在5-FU后再生的P53-/-BMCs中，不同谱系特异性后代的克隆形成活性显著高于P53+/+BMCs，这可能是因为它们对生长因子的敏感性增加。尽管这些变化以及P53-/-和P53+/+BMCs对5-FU诱导的凋亡的敏感性存在显著差异，但造血祖细胞的谱系承诺和分化似乎与P53状态无关，这些研究表明，抑制P53功能可通过以下方式促进细胞减少治疗后的造血重建：(1)延缓最原始HSC池的耗竭，(2)刺激多潜能HSC的产生，(3)增加造血细胞对生长因子的敏感性，以及(4)降低对凋亡的敏感性。(C)1998年由美国血液病学会主办。
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 (CPU-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. (C) 1998 by The American Society of Hematology.