title: Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen.
abstract: BACKGROUND
  Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.
  
  
  METHODS
  A Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.
  
  
  RESULTS
  More leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3β was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3β recruits T-ALL cells which express a high level of MIP-3β receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3β, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.
  
  
  CONCLUSIONS
  Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. msh257257@163.com.
authors.forename: Shihui
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. shi.yingxu.wolf@gmail.com.|Current address of Yingxu Shi: Affiliated Hospital Clinical Laboratory, Inner Mongolian Medical University, Hohhot, China. shi.yingxu.wolf@gmail.com.
authors.forename: Yingxu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. pangyakun6@163.com.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. dfh831229@sina.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. chenghui.pumc@gmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. sha.hao@hotmail.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. Alice_Xu12@hotmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. xfzhu1981@126.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China. xfzhu1981@126.com.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. weiping.yuan@gmail.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, 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 Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. chengt@pumc.edu.cn.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China. chengt@pumc.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. zhengggtjchn@aliyun.com.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China. zhengggtjchn@aliyun.com.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D013154:Spleen / Q000473:pathology*; D013156:Splenectomy; D059016:Tumor Microenvironment
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1