title: Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow.
abstract: Degeneration of normal hematopoietic cells is a shared feature of malignant diseases in the hematopoietic system. Previous studies have shown the exhaustion of hematopoietic progenitor cells (HPCs) in leukemic marrow, whereas hematopoietic stem cells (HSCs) remain functional upon relocation to non-leukemic marrow. However, the underlying cellular mechanisms, especially the specific niche components that are responsible for the degeneration of HPCs, are unknown. In this study, we focused on murine bone mesenchymal stem cells (MSCs) and their supporting function for normal hematopoietic cells in Notch1-induced acute T-cell lymphocytic leukemia (T-ALL) mice. We demonstrate that the proliferative capability and differentiation potential of T-ALL MSCs were impaired due to accelerated cellular senescence. RNA-seq analysis revealed significant transcriptional alterations in leukemic MSCs. After co-cultured with the MSCs from T-ALL mice, a specific inhibitory effect on HPCs was defined, whereas in vivo repopulating potential of normal HSCs was not compromised. Furthermore, osteoprotegerin was identified as a cytokine to improve the function of T-ALL MSCs and to enhance normal HPC output via the p38/ERK pathway. Therefore, this study reveals a novel cellular mechanism underlying the inhibition of HPC generation in T-ALL. Leukemic MSCs may serve as a cellular target for improving normal hematopoietic regeneration therapeutically.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.
authors.forename: M
authors.initials: M
authors.lastname: Lim
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.
authors.forename: Y
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 Colleage, Tianjin, China.
authors.forename: S
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 Colleage, Tianjin, China.
authors.forename: S
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 Colleage, Tianjin, China.
authors.forename: H
authors.initials: H
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 Colleage, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Hua
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Gu
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.
authors.forename: W
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 Colleage, Tianjin, China.|Center for Stem Cell Medicine and Department of Stem Cell & Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China.|Collaborative Innovation Center for Cancer Medicine, Tianjin, China.
authors.forename: T
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053244:Osteoprotegerin / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
chemical_list: D053244:Osteoprotegerin