Adult hematopoietic stem cells require NKAP for maintenance and survival

Anthony G. Pajerowski, Michael J. Shapiro, Kimberly Gwin, Rhianna Sundsbak, Molly Nelson-Holte, Kay L Medina, Virginia M Shapiro

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2684-2693
Number of pages10
JournalBlood
Volume116
Issue number15
DOIs
StatePublished - Oct 14 2010

Fingerprint

Adult Stem Cells
Hematopoietic Stem Cells
Stem cells
Maintenance
Hematopoiesis
Radiation Chimera
Bone
Bone Marrow
Radiation
Megakaryocytes
Lymphocytes
Cyclin-Dependent Kinases
Granulocytes
Knockout Mice
Embryonic Development
Cell Survival
Erythrocytes
Apoptosis
Defects

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Pajerowski, A. G., Shapiro, M. J., Gwin, K., Sundsbak, R., Nelson-Holte, M., Medina, K. L., & Shapiro, V. M. (2010). Adult hematopoietic stem cells require NKAP for maintenance and survival. Blood, 116(15), 2684-2693. https://doi.org/10.1182/blood-2010-02-268391

Adult hematopoietic stem cells require NKAP for maintenance and survival. / Pajerowski, Anthony G.; Shapiro, Michael J.; Gwin, Kimberly; Sundsbak, Rhianna; Nelson-Holte, Molly; Medina, Kay L; Shapiro, Virginia M.

In: Blood, Vol. 116, No. 15, 14.10.2010, p. 2684-2693.

Research output: Contribution to journalArticle

Pajerowski, AG, Shapiro, MJ, Gwin, K, Sundsbak, R, Nelson-Holte, M, Medina, KL & Shapiro, VM 2010, 'Adult hematopoietic stem cells require NKAP for maintenance and survival', Blood, vol. 116, no. 15, pp. 2684-2693. https://doi.org/10.1182/blood-2010-02-268391
Pajerowski AG, Shapiro MJ, Gwin K, Sundsbak R, Nelson-Holte M, Medina KL et al. Adult hematopoietic stem cells require NKAP for maintenance and survival. Blood. 2010 Oct 14;116(15):2684-2693. https://doi.org/10.1182/blood-2010-02-268391
Pajerowski, Anthony G. ; Shapiro, Michael J. ; Gwin, Kimberly ; Sundsbak, Rhianna ; Nelson-Holte, Molly ; Medina, Kay L ; Shapiro, Virginia M. / Adult hematopoietic stem cells require NKAP for maintenance and survival. In: Blood. 2010 ; Vol. 116, No. 15. pp. 2684-2693.
@article{b903cc25ec404b28991acd56ad869d6b,
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.",
author = "Pajerowski, {Anthony G.} and Shapiro, {Michael J.} and Kimberly Gwin and Rhianna Sundsbak and Molly Nelson-Holte and Medina, {Kay L} and Shapiro, {Virginia M}",
year = "2010",
month = "10",
day = "14",
doi = "10.1182/blood-2010-02-268391",
language = "English (US)",
volume = "116",
pages = "2684--2693",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",

}

TY - JOUR

T1 - Adult hematopoietic stem cells require NKAP for maintenance and survival

AU - Pajerowski, Anthony G.

AU - Shapiro, Michael J.

AU - Gwin, Kimberly

AU - Sundsbak, Rhianna

AU - Nelson-Holte, Molly

AU - Medina, Kay L

AU - Shapiro, Virginia M

PY - 2010/10/14

Y1 - 2010/10/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957943998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957943998&partnerID=8YFLogxK

U2 - 10.1182/blood-2010-02-268391

DO - 10.1182/blood-2010-02-268391

M3 - Article

C2 - 20610818

AN - SCOPUS:77957943998

VL - 116

SP - 2684

EP - 2693

JO - Blood

JF - Blood

SN - 0006-4971

IS - 15

ER -