hsutherl@interchange.ubc.ca
 hsutherl@bccancer.bc.ca

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Research Interests:

The production of normal blood cells is a hierarchical process of regulated proliferation and differentiation with co-ordinate loss of self-renewal potential of bone marrow progenitors. The most primitive of such cells, the stem cells, are defined in the mouse by their ability to reconstitute lymphomyelopoiesis in marrow-ablated recipients. These cells copurify with cells which generate clonogenic progenitors after many weeks in culture in the presence of a marrow stromal adherent layer, and which have been called long term culture-initiating cells (LTC-IC).

Using this defined functional assay, the cell surface phenotype of these primitive cells can be defined and thus highly purified populations obtained using cell sorting. These populations are used for studies of their growth factor regulation, and studies of molecular events which may be controlling their development.

Currently studies in my laboratory are exploring the hypothesis that hemato-logical malignancies are derived from transformation of one of these primitive hematopoietic progenitors which, despite their transformed nature, undergo subsequent differentiation prior to maturation arrest.

Only a minority of the blasts seen in the blood and bone marrow of acute myeloid leukemia (AML) patients proliferate in vitro, and it is likely that a relatively rare AML stem cell is responsible for maintaining the disease seen in vivo. We are developing assays for these cells in vitro and in immunodeficient NOD/SCID mice, and are developing a purification strategy for these cells using monoclonal antibodies and a fluorescence activated cell sorter (FACS). Using these purified cell populations, the biological and molecular characteristics of leukemic stem cells will be compared with those of normal stem cells. Differences may direct investigation of candidate molecular events resulting in transformation.

Evidence for heterogeneity within the malignant clone also exists for multiple myeloma with both very primitive and mature lymphoid cells with the idiotypic rearrangement detectable. We are evaluating functional assays for clonogenic myeloma cells and are developing ways of detecting small numbers of these cells using PCR. The first immediate objective of these studies is to develop monoclonal antibody based purging strategies to remove both total and clonogenic myeloma cells from blood or marrow autografts.

Additionally, in collaboration with others, we are evaluating the hematopoietic progenitors which can be mobilized into the peripheral blood. Blood cells collected from patients or normal donors after growth factor treatment or during their recovery from chemotherapy are now being used for transplantation after marrow ablative treatment. We are interested in identifying differences which might exist between bone marrow and mobilized blood in vivo repopulating cells and identifying optimal mobilization strategies to obtain high concentrations of very primitive cells useful for transplantation.