title: FHL2 regulates hematopoietic stem cell functions under stress conditions.
abstract: FHL2, a member of the four and one half LIM domain protein family, is a critical transcriptional modulator. Here, we identify FHL2 as a critical regulator of hematopoietic stem cells (HSCs) that is essential for maintaining HSC self-renewal under regenerative stress. We find that Fhl2 loss has limited effects on hematopoiesis under homeostatic conditions. In contrast, Fhl2-null chimeric mice reconstituted with Fhl2-null bone marrow cells developed abnormal hematopoiesis with significantly reduced numbers of HSCs, hematopoietic progenitor cells (HPCs), red blood cells and platelets as well as hemoglobin levels. In addition, HSCs displayed a significantly reduced self-renewal capacity and were skewed toward myeloid lineage differentiation. We find that Fhl2 loss reduces both HSC quiescence and survival in response to regenerative stress, probably as a consequence of Fhl2-loss-mediated downregulation of cyclin-dependent kinase-inhibitors, including p21(Cip) and p27(Kip1). Interestingly, FHL2 is regulated under the control of a tissue-specific promoter in hematopoietic cells and it is downregulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells. Furthermore, we find that downregulation of FHL2 frequently occurs in myelodysplastic syndrome and acute myeloid leukemia patients, raising a possibility that FHL2 downregulation has a role in the pathogenesis of myeloid malignancies.
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Hematology, Fudan University Huashan Hospital, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA [2] Fudan University ZhongShan Hospital, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, Fudan University Huashan Hospital, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Fudan University ZhongShan Hospital, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA [2] Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mittal
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Peace
authors.affiliation: Department of Medicine and Cancer Research Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Qian
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C105987:FHL2 protein, human; C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27