title: Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation.
abstract: Cytopenias resulting from the impaired generation of normal blood cells from hematopoietic precursors are important contributors to morbidity and mortality in patients with leukemia. However, the process by which normal hematopoietic cells are overtaken by emerging leukemia cells and how different subsets of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are distinctly influenced during leukemic cell infiltration is poorly understood. To investigate these important questions, we used a robust nonirradiated mouse model of human MLL-AF9 leukemia to examine the suppression of HSCs and HPCs during leukemia cell expansion in vivo. Among all the hematopoietic subsets, long-term repopulating HSCs were the least reduced, whereas megakaryocytic-erythroid progenitors were the most significantly suppressed. Notably, nearly all of the HSCs were forced into a noncycling state in leukemic marrow at late stages, but their reconstitution potential appeared to be intact upon transplantation into nonleukemic hosts. Gene expression profiling and further functional validation revealed that Egr3 was a strong limiting factor for the proliferative potential of HSCs. Therefore, this study provides not only a molecular basis for the more tightened quiescence of HSCs in leukemia, but also a novel approach for defining functional regulators of HSCs in disease.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Yakun
authors.initials: Y
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Shihui
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Fang
authors.initials: F
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China;
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017254:Leukemic Infiltration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D013154:Spleen / Q000473:pathology
chemical_list: C497369:Egr3 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051776:Early Growth Response Protein 3