title: The NFKB Inducing Kinase Modulates Hematopoiesis During Stress.
abstract: The genetic programs that maintain hematopoiesis during steady state in physiologic conditions are different from those activated during stress. Here, we show that hematopoietic stem cells (HSCs) with deficiencies in components of the alternative NFκB pathway (the NFκB inducing kinase, NIK, and the downstream molecule NFκB2) had a defect in response to stressors such as supraphysiological doses of cytokines, chemotherapy, and hematopoietic transplantation. NIK-deficient mice had peripheral blood and bone marrow leukocyte numbers within normal ranges (except for the already reported defects in B-cell maturation); however, HSCs showed significantly slower expansion capacity in in vitro cultures compared to wild-type HSCs. This was due to a delayed cell cycle and increased apoptosis. In vivo experiments showed that NIK-deficient HSCs did not recover at the same pace as controls when challenged with myeloablative chemotherapy. Finally, NIK-deficient HSCs showed a significantly decreased competitive repopulation capacity in vivo. Using HSCs from mice deficient in one of two downstream targets of NIK, that is, either NFκB2 or c-Rel, only NFκB2 deficiency recapitulated the defects detected with NIK-deficient HSCs. Our results underscore the role of NIK and the alternative NFκB pathway for the recovery of normal levels of hematopoiesis after stress.
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: África
authors.initials: Á
authors.lastname: González-Murillo
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Fernández
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Baena
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.affiliation: Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sánchez
authors.affiliation: Cell Biology and Immunology department, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Valdepeñas
authors.affiliation: Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Segovia
authors.affiliation: Immunology, Cornell University Medical College, New York, New York, USA.
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
authors.affiliation: II, Medizinische Klinik, Technische Universität, Munich, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmid
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Luís
authors.initials: L
authors.lastname: Madero
authors.affiliation: Cell Biology and Immunology department, Centro de Biología Molecular Severo Ochoa, Cantoblanco, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.affiliation: Laboratorio de Oncología, Oncohematología, FIB Hospital Universitario Niño Jesús, and Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramírez
mesh_terms: D000818:Animals; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C498207:Nfkb2 protein, mouse
keywords: Adult hematopoietic stem cells; Apoptosis; Cellular proliferation; Hematopoietic stem cell transplantation