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.
- Hematopoietic stem cells engraft in mice with absolute efficiency. P Benveniste, C Cantin, D Hyam and NN Iscove. Nature Immunology 4:708-713, 2003.
- 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.
- 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.
- Under review Sept 2015.