Excessive proliferation and impaired function of primitive hematopoietic cells in bone marrow due to senescence post chemotherapy in a T cell acute lymphoblastic leukemia model.
Excessive proliferation and impaired function of primitive hematopoietic cells in bone marrow due to senescence post chemotherapy in a T cell acute lymphoblastic leukemia model.
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在 T 细胞急性淋巴细胞白血病模型中，化疗后衰老导致骨髓中原始造血细胞过度增殖和功能受损。
DOI：
10.1186/s12967-015-0543-8
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发表时间：
2015-07-17
影响因子：
7.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Jiang C;Hu X;Wang L;Cheng H;Lin Y;Pang Y;Yuan W;Cheng T;Wang J
在临床环境中，复发性白血病患者由于造血恢复延迟或不完全而对化疗更加脆弱，并且这些患者的造血功能似乎受到损害。我们采用非照射T细胞急性淋巴细胞白血病小鼠模型联合阿糖胞苷和环磷酰胺建立了白血病治疗模型。全面研究化疗应激下白血病宿主原始造血细胞和白血病细胞的动态动力学和功能状态。我们成功建立了T淋巴细胞表型的白血病治疗模型。阿糖胞苷和环磷酰胺治疗后，L−K+S+造血细胞的频率随治疗而变化，疾病缓解时稳定，复发时减少，而白血病细胞则表现出延迟但一致的再生。联合化疗可显着促进 L−K+S+ 造血细胞早期短暂进入活跃增殖状态，并诱导体内 L−K+S+ 细胞凋亡。此外，在竞争性骨髓移植试验中，造血细胞的再生能力逐渐减弱。衰老相关 β-半乳糖苷酶 (SA-β gal) 状态的测试显示，与对照组相比，治疗后 L−K+S+ 造血细胞中的水平更高。造血原始细胞的基因表达分析显示 p16、p21 上调，egr1 和 fos 下调。我们得出的结论是，化疗后骨髓中的原始造血细胞比白血病细胞更早进入增殖，并逐渐丧失再生能力，部分原因是加速循环导致的衰老。本文的在线版本 (doi:10.1186/s12967-015-0543-8) 包含补充材料，可供授权用户使用。
In clinic settings, rel apsed leukemic patients are found to be more fragile to chemotherapy due to delayed or incomplete hematopoietic recovery, and hematopoiesis of these patients seem to be impaired. We established a leukemia therapy model with a non-irradiated T cell acute lymphoblastic leukemia mouse model combined with cytarabine and cyclophosphamide. Dynamic kinetics and functional status of both primitive hematopoietic cells and leukemic cells in a leukemia host under the chemotherapy stress were comprehensively investigated. We successfully established the leukemia therapy model with T lymphoblastic phenotype. After treatment with cytarabine and cyclophosphamide, the frequency of L−K+S+ hematopoietic cells tides with the therapy, and stabled when the disease remission, then reduced when relapsed, while leukemic cells showed a delayed but consistent regeneration. Combination of chemotherapy significantly promote an early and transient entrance of L−K+S+ hematopoietic cells into active proliferation and induction of apoptosis on L−K+S+ cells in vivo. Moreover, in the competitive bone marrow transplantation assays, hematopoietic cells showed gradually diminished regenerative capacity. Testing of senescence-associated beta-galactosidase (SA-β gal) status showed higher levels in L−K+S+ hematopoietic cells post therapy when compared with the control. Gene expression analysis of hematopoietic primitive cells revealed up-regulated p16, p21, and down-regulated egr1 and fos. We conclude that primitive hematopoietic cells in bone marrow enter proliferation earlier than leukemic cells after chemotherapy, and gradually lost their regenerative capacity partly by senescence due to accelerated cycling. The online version of this article (doi:10.1186/s12967-015-0543-8) contains supplementary material, which is available to authorized users.