title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. smmujch121611@163.com.
authors.forename: Chuanhe
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. hu-xiaoxia@126.com.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. doctorwanglibing@126.com.
authors.forename: Libing
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. chenghui19831103@163.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. chenghui19831103@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. thelma-linyan@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. pangyakunb@163.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. pangyakunb@163.com.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. weiping.yuan@gmail.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. weiping.yuan@gmail.com.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. chengt@pumc.edu.cn.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. chengt@pumc.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Institute of Hematology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. jmwang@medmail.com.cn.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology*