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

Stem cell reports 2014 Nov 11

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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.

Citation

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. A dominant-negative isoform of IKAROS expands primitive normal human hematopoietic cells. Stem cell reports. 2014 Nov 11;3(5):841-57