Norman N Iscove

Norman N Iscove, PhD, MD

Genetic regulation of self-renewal and differentiation in normal and leukemic hematopoiesis

The production of blood cells and lymphocytes is maintained throughout life from rare multipotential hematopoietic stem cells in the bone marrow. When stem cells enter active growth, they generate two kinds of progeny. Some are pre-programmed to differentiate. Other progeny, generated in a process known as self-renewal, remain as stem cells, thereby guaranteeing the persistence of stem cells and the permanence of blood cell formation.

Competition between self-renewal and differentiation of rare stem cells is a feature common to the maintenance not only of most normal tissues but also of most cancers. Sustained growth of malignant tumours is thus viewed as similarly dependent on the process of self-renewal. Our work is concerned with the genes and mechanisms that specify self-renewal and differentiation in normal and leukemic hematopoietic stem cells.

Recent progress includes:
  • discovery of a new, non-permanent category of stem cells (1,2),
  • delineation of a role for the Gata3 transcription factor in regulating stem cell self-renewal (3), and
  • demonstration of the central role of the clustered Homeobox genes in governing the amount of permitted proliferation throughout the marrow precursor hierarchy (4).
An exciting projection of these findings concerns the beginnings of leukemia. Currently ongoing work tests the notion that leukemia begins with a first mutation in a marrow precursor cell that extends its lifespan, that the persistence of growing leukemia cells depends on the same first mutation, and that disrupting the first mutation could provide a pathway to leukemia cure.

More detail about these projects can be found on Dr. Iscoves's lab webpage.
 
Selected Publications
  1. Hematopoietic stem cells engraft in mice with absolute efficiency. P Benveniste, C Cantin, D Hyam and NN Iscove. Nature Immunology 4:708-713, 2003.
  2. Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential. P Benveniste, C Frelin, S Janmohamed, M Barbara, R Herrington, D Hyam and NN Iscove. Cell Stem Cell 6:48-58, 2010.
  3. Gata-3 regulates the self-renewal of long-term hematopoietic stem cells. C Frelin, R Herrington, S Janmohamed, M Barbara, G Tran, CJ Paige, P Benveniste, JC Zuñiga-Pflücker, A Souabni, M Busslinger and NN Iscove. Nature Immunology 14:1037-44, 2013.
  4. Under review Sept 2015.

Related Links

Cell Stem Cell. 2015 Feb 18;
Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, Neumann A, Plumb I, Doulatov S, Chen J, April C, Fan JB, Iscove N, Dick JE
Science. 2014 Sep 19;345(6203):1509-12
Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N, Csaszar E, Knapp DJ, Miller P, Ngom M, Imren S, Roy DC, Watts KL, Kiem HP, Herrington R, Iscove NN, Humphries RK, Eaves CJ, Cohen S, Marinier A, Zandstra PW, Sauvageau G
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20599-604
Louria-Hayon I, Frelin C, Ruston J, Gish G, Jin J, Kofler MM, Lambert JP, Adissu HA, Milyavsky M, Herrington R, Minden MD, Dick JE, Gingras AC, Iscove NN, Pawson T
Nat Med. 2014 Jan;20(1):29-36
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O'Brien CA
Cell. 2013 Sep 26;155(1):215-27
Chanda B, Ditadi A, Iscove NN, Keller G
Nat Immunol. 2013 Oct;14(10):1037-44
Frelin C, Herrington R, Janmohamed S, Barbara M, Tran G, Paige CJ, Benveniste P, Zuñiga-Pflücker JC, Souabni A, Busslinger M, Iscove NN
PLoS One. 2013;8(3):e58787
Berger A, Frelin C, Shah DK, Benveniste P, Herrington R, Gerard NP, Zúñiga-Pflücker JC, Iscove NN, Paige CJ
PLoS One. 2013;8(1):e53161
Ohno Y, Yasunaga S, Janmohamed S, Ohtsubo M, Saeki K, Kurogi T, Mihara K, Iscove NN, Takihara Y
Blood. 2012 Mar 15;119(11):2510-22
Ting SB, Deneault E, Hope K, Cellot S, Chagraoui J, Mayotte N, Dorn JF, Laverdure JP, Harvey M, Hawkins ED, Russell SM, Maddox PS, Iscove NN, Sauvageau G

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Professor, Department of Medical Biophysics, University of Toronto