title: A dominant-negative isoform of IKAROS expands primitive normal human hematopoietic cells.
abstract: Disrupted IKAROS activity is a recurrent feature of some human leukemias, but effects on normal human hematopoietic cells are largely unknown. Here, we used lentivirally mediated expression of a dominant-negative isoform of IKAROS (IK6) to block normal IKAROS activity in primitive human cord blood cells and their progeny. This produced a marked (10-fold) increase in serially transplantable multipotent IK6(+) cells as well as increased outputs of normally differentiating B cells and granulocytes in transplanted immunodeficient mice, without producing leukemia. Accompanying T/natural killer (NK) cell outputs were unaltered, and erythroid and platelet production was reduced. Mechanistically, IK6 specifically increased human granulopoietic progenitor sensitivity to two growth factors and activated CREB and its targets (c-FOS and Cyclin B1). In more primitive human cells, IK6 prematurely initiated a B cell transcriptional program without affecting the hematopoietic stem cell-associated gene expression profile. Some of these effects were species specific, thus identifying novel roles of IKAROS in regulating normal human hematopoietic cells.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Miller
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bulaeva
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nima
authors.initials: N
authors.lastname: Aghaeepour
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rabu
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Rostamirad
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Kingsley
authors.initials: K
authors.lastname: Shih
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wei
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada. Electronic address: ceaves@bccrc.ca.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C586512:Ikaros 6 protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor