The development of leukemia involves a sequential series of mutational events involving primitive cells within the bone marrow that normally serve as stem cells capable of both self-renewal (i.e. sustaining a small reserve population of undifferentiated cells) and differentiating into all the different blood cell lineages.
A genetic change necessary in all successful cancers is the development of immortality. All normal cells, including stem cells, are limited in the number of cell divisions they can undergo (Hayflick limit) and will eventually undergo terminal senescence. In contrast, in acute leukemias (but not in chronic leukemias) cells are immortal and can undergo indefinite replication.
Over the last two years the laboratory has been maintaining the H1 human ES cell line and developing conditions for inducing its differentiation into hematopoietic lineage, lymphoid lineage (including T cell differentiation) and endothelial lineage. By using combinations of cytokines (thrombopoietin, VEGF, cKit ligand, Flt3 ligand, IL-7) and morphogens (BMP’s, Notch ligands) and modifying homeobox protein levels or STAT5 signaling pathways, we are developing systems for generation of human hematopoietic stem cells with the capacity to engraft in NOD/SCID mice.
The laboratory has an active program for ex vivo culture and expansion of hematopoietic stem cells from adult marrow, G-CSF mobilized peripheral blood and umbilical cord blood for potential use for unrelated donor transplantation for treatment of leukemia, lymphoma and multiple myeloma, aplastic anemia and genetic disorders of the hematopoietic and immune system.
This program has a number of objectives involving characterization and genetic manipulation of endothelial stem cells and differentiated endothelium using retro- and adenoviral gene delivery systems. We are also evaluating anti-angiogenesis therapy in human tumor models.
In collaboration with Dr. S. Rafii (Weill Medical College) we observed that prolonged in vitro culture of stem cells leads to downregulation of their CXCR4 with reduction in transendothelial chemotaxis and in vivo engraftment potential. We are evaluating cytokines that can upregulate or stabilize CXCR4 expression (IL-6, IL-11, TNF), and cytokines that downmodulate and impair chemotaxis (IL-3).
Research in the laboratory, particularly into hematopoietic malignancies (leukemia, lymphoma and multiple myeloma) as well as into the process of metastasis in various solid tumor systems, continues to identify potential therapeutic targets. Consequently a program has been established to validate these targets and identify novel therapeutic agents that can be moved into clinical trial.