The E. Donnall Thomas Lecture-
a Chronicle of Growth Factor Discovery

Hematopoietic growth factors and other regulators of hematopoiesis have been prominently featured this year at ASH. An exciting and informative scientific committee session, offered Saturday and Sunday, brought together three leading experts who covered the interplay between chemokines and growth factors and the effects of these factors on the development, homing, survival, localization, and differentiation on hematopoietic stem cells. Today, the E. Donnall Thomas Lecture at 9:30 a.m. presents Dr. Donald Metcalf from the Walter and Eliza Hall Institute of Medical Research, a scientist who has given the field of hematology numerous key contributions and seminal discoveries over the last four decades. This lecture promises to be a real treat for everyone and a fast moving chronicle of various technologies used by the Metcalf group to identify and clone growth factors and bring those to the bedside in clinical trials.

The Hematopoietic Growth Factors Scientific Committee Session began with a discussion of the role of CD26, SDF-1 (CXCL12), and CXCR4 in homing and engraftment of stem cells by Dr. Hal E. Broxmeyer (Indiana University). Dr. Broxmeyer documented how the dipeptidylpeptidase IV activity of CD26 truncates SDF-1 producing an altered chemokine that blocks the activity of full length SDF- 1 and interferes with its normal chemotactic activity. Inhibition of CD26 activity promotes homing of murine hematopoietic stem cells to the marrow and enhances engraftment in both competitive and non-competitive repopulation assays suggesting a clear practical implication for such interventions. The role of CXCL12 in the ontogeny of the hematopoietic system was discussed by Dr. Takashi Nagasawa (Kyoto University) who mapped out the expression of SDF-1 by different cells in different hematopoietic microenvironments in the developing fetus. The spatial relationship between SDF-1 expressing cells, SCF/IL-7 expressing cells, and B lymphocytes of varying maturational age generate stage-specific niches for B lymphopoiesis. The session concluded with Dr. Shahin Rafii (Cornell University) who outlined the role of chemokines in hematopoietic reconstitution. He demonstrated how chemokine-mediated haptotactic activation of adhesion molecules provides directional cues required for the recruitment of hematopoietic stem cells from the bone marrow osteoblastic niches to the vascular niche, a relocalization step essential for rapid reconstitution of early phases of hematopoiesis. Dr. Rafii also addressed the potential clinical applications of these results and the role chemokines may play in stimulating lineage-specific hematopoiesis.

In today’s lecture, Dr. Metcalf will review the history of discovery steps leading to the clinical use of the colony stimulating factors and erythropoietin. He will discuss how, in the quest for identifying regulators of hematopoiesis, gene deletion studies established that these growth factors were essential players in the regulatory network of hematopoiesis, but other, yet unidentified regulatory elements remain elusive. Dr. Metcalf will describe more recent attempts to identify the new missing regulators of hematopoiesis and illustrate that many of the hematopoietic growth factors are not restricted in their activity to the hematopoietic system, there thus lies one of the major problems in this field. Dr. Metcalf will conclude by covering three recent strategies to discover the missing hematopoietic regulators. First, cloning of receptors and matching those with their ligands, a process which did not reveal new regulators. Second, clonal screening, an approach that led to the discovery of the SOCS family of inducible suppressors of hematopoiesis, and finally, mutagenesis by ENU of genetically manipulated mice. This final methodology identified the actions of known oncogenes on hematopoiesis, but has not yet identified any new regulators. Dr. Metcalf will conclude his lecture by stressing that, most likely, many unknown regulators remain unspecified and therefore restrict our potential for the discovery of clinically efficient agents. If you enjoy a ride through many important and pivotal scientific and clinical discoveries in the field of hematopoiesis, be sure to attend the E. Donnell Thomas Lecture today.