Dr. Downing’s career has followed the path of a physician scientist, integrating clinical work with basic laboratory investigations in molecular pathology. Specifically, he has taken clinical observations and explored their underlying molecular pathology in a basic research setting, and has taken basic research observations or methodologies and pursued their translation into diagnostic assays. The major theme of his work has been to investigate the fundamental regulatory mechanisms that control normal and leukemic hematopoiesis.

Dr. Downing’s early work focused on the characterization of the signal transduction pathway of receptor tyrosine kinases. In collaborative studies with Dr. Charles Sherr at St. Jude Children’s Research Hospital, he demonstrated that ligand-binding induced dimerization of the receptor for the monocyte specific colony stimulating factor (CSF-1), a receptor tyrosine kinase. This dimerization in turn was shown to induce a conformational change in the intracellular domain of the receptor, resulting in kinase activation and receptor cross-phosphorylation. He went on to identify some of the downstream targets of the activated receptor tyrosine kinase involved in propagating its proliferative signal. Moreover, he was involved in early studies that defined how oncogenic mutations in tyrosine kinase receptors lead to constitutive activation of the receptor. These studies provided some of the initial groundwork for what is now a well-accepted paradigm for receptor tyrosine kinase signaling, and the role of alterations in this pathway in human cancers.

More recently, the major theme of his work has been to the investigation of the role of chromosomal translocations in the pathogenesis of pediatric malignancies. Dr. Downing has established one of the premiere clinical Molecular Diagnostic Laboratories within the United States. This laboratory performs a wide range of molecular diagnostic assays and has played a lead role in incorporating these assays into frontline patient management. Spurred on by observations made within his clinical laboratory on pediatric leukemias, Dr. Downing has focused his basic laboratory studies on the investigation of the fundamental regulatory mechanisms that control normal and leukemic hematopoiesis. In collaborative studies with Dr. Scott Hiebert, his laboratory demonstrated that the AML1 gene, one of the most common targets of chromosomal rearrangements in acute leukemias, is a transcription factor that regulates the transcription of a large number of hematopoietic specific target genes through the core enhancer sequence. He went on to demonstrate through the generation of AML1-deficient mice, that the AML1/CBFß transcription factor complex is a master regulator that controls the formation of definitive hematopoietic stem cells. Moreover, using gene-targeting methodologies, he has generated an elegant murine model of t(8;21)-containing acute myeloid leukemia. This model has demonstrated that the AML1-ETO fusion protein, contrary to the current paradigm, does not block differentiation, but instead is responsible for increasing the self-renewal capacity of early hematopoietic progenitors. This model will provide a unique reagent for the evaluation of novel targeted therapies to this common form of leukemia.

His basic work on the AML1/CBFß transcription factor complex led to a search for alteration in the genes encoding this complex in pediatric acute Lymphoblastic leukemia. In collaborative studies with Dr. Gerard Grosveld, Dr. Downing demonstrated that AML1 was the target of a t(12;21) translocation found in pediatric early B-cell lineage pediatric (ALL). Using molecular diagnostic approaches, he then demonstrated that this was the most common translocation found on pediatric ALL, and identified a subgroup of patients with an excellent prognosis. This information is now used in risk-stratifying patients at the time of diagnosis. More recently, Dr. Downing has extended the molecular analysis of leukemias to the use of gene expression profiling using microarrays. His group has published one of the largest studies on the use of this methodology to explore the molecular pathology of human cancers. Their analysis demonstrated that the single platform of gene expression profiling could accurately identify the known prognostic subgroups of pediatric ALL. Moreover, the expression profiling provided unique insights into the oncogenic lesions responsible for the transformation of the hematopoietic stem cells. This exciting work will not only improve our ability to accurately classify leukemias, but should also lead to the identification of novel targets against which new therapies can be developed.

Dr. Downing’s scholarly activities have resulted in over 110 papers published in peer-reviewed journals and 8 book chapters. He is a frequent invited speaker at National and International symposia, and has developed a reputation as an outstanding speaker and educator. He is an active participant in the USCAP and served as a member of the Education Committee from 1996-2000, and as the Director of the Academy’s special course in Molecular Pathology from 1997-2001. Dr. Downing has been the recipient of a number of prestigious awards, including membership in the Society of Clinical Investigation, the Young Investigator Award from the USCAP in 1996, and the Alumni of the year award from the University of Michigan – Dearborn in 1999. In addition, Dr. Downing serves on editorial boards for several scientific journals including Leukemia and Cancer Cell.