A dominant-negative isoform of IKAROS expands primitive normal human hematopoietic cells

Philip A. Beer, David J.H.F. Knapp, Nagarajan Kannan, Paul H. Miller, Sonja Babovic, Elizabeth Bulaeva, Nima Aghaeepour, Gabrielle Rabu, Shabnam Rostamirad, Kingsley Shih, Lisa Wei, Connie J. Eaves

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)841-857
Number of pages17
JournalStem Cell Reports
Volume3
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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