The laboratory undertakes research on the hematopoietic stem cells and progenitor populations, in normal mice and humans, and in neoplastic and genetic diseases. The laboratory has a long history of the using in vitro clonogenic assays for characterization of factors (e.g. G-CSF) involved in differentiation of hematopoietic progenitor cells into mature cells (Fig1). Subsequent studies, utilizing in vitro stem cell assays (Fig 2), have been directed at factors influencing stem cell proliferation, particularly cytokines favoring self-renewal rather than differentiation (ligands for c-Kit and flk2/flt3, Interleukins-1, -6, -11, thrombopoietin). Currently, retroviral, lentiviral and adenoviral gene delivery systems are being used to modify human stem cells self-renewal, differentiation and migration by introduction of genes for telomerase, Notch, CXCR4 and the HOX family. The process of leukemogenesis is being studied by transduction of normal human stem cells with leukemogenic genes such as bcr-abl, AML-ETO, Nup98/HOXA9 and mutated forms of Flt3 and Ras.
The hematopoietic microenvironment plays a critical role in orchestrating the homing of stem cells and their subsequent proliferation and differentiation. It does so by elaborating a number of hematopoietic growth stimulatory and inhibitory factors including cytokines, chemokines and morphogens. These are under active investigation, and genetically modified stromal cell populations are being developed to optimize stem cell expansion, or specific lineage differentiation such as B cell, NK cell, dendritic, megakaryocytic etc. We are evaluating the differentiation potential of subpopulations of primitive marrow cells. These studies are designed to determine the plasticity of stem cells and the developmental interrelationships of various stem cell types, including those expressing the vascular endothelial growth factor receptor, and totipotential stem cells represented by murine, primate and human embryonic stem cell lines. Research into human embryonic stem cells is directed into understanding the steps involved in the differentiation of the totipotent cells into hemangioblasts, and subsequently into hematopoietic stem cells and endothelial progenitors with functional capacity in vivo using xenografted immunodeficient NOD/SCID mice.
The laboratory is involved in a number of translational projects using human tumor xenografts models of orthotopic or disseminated human tumor cell lines in NOD/SCID mice in conjunction with whole body luciferase imaging technology. We are currently employing panels of human hematopoietic tumor lines (lymphoma, multiple myeloma, acute myeloid leukemia) and solid tumors (ovarian, breast, colorectal,) and evaluating therapeutic antibodies directed against receptors (VEGF receptors, Insulin-like growth factor receptors, Flt3 receptors). We are also evaluating small molecules targeting telomerase or tyrosine kinases, antagonists of HSP90 or CXCR4, and synthetic analogs of epothilone and migrastatin.
Experimental Hematology Research
This laboratory undertakes research on hematopoietic stem cells and progenitor populations, in normal mice and humans, and in neoplastic and genetic diseases.