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

Journal of Translational Medicine

Jianmin Wang¹  Tao Cheng²  Weiping Yuan²  Yakun Pang²  Yan Lin¹  Hui Cheng²  Libing Wang¹  Xiaoxia Hu¹  Chuanhe Jiang¹ 

[1] Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China

关键词: Senescence;    Chemotherapy;    Leukemia;    Primitive hematopoietic cells;   

Others  :  1221447
DOI  :  10.1186/s12967-015-0543-8

 received in 2015-03-24, accepted in 2015-05-18,  发布年份 2015

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2015 Jiang et al.

【 图 表 】

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