title: Adult hematopoietic stem cells require NKAP for maintenance and survival.
abstract: Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival.
authors.affiliation: Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Pajerowski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gwin
authors.forename: Rhianna
authors.initials: R
authors.lastname: Sundsbak
authors.forename: Molly
authors.initials: M
authors.lastname: Nelson-Holte
authors.forename: Kay
authors.initials: K
authors.lastname: Medina
authors.forename: Virginia Smith
authors.initials: VS
authors.lastname: Shapiro
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011828:Radiation Chimera
chemical_list: C493957:Cdkn1a protein, mouse; D056970:Co-Repressor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D012333:RNA, Messenger