Janis Abkowitz, MD
Professor and Head, Division of Hematology, Dept of Medicine
A major focus of Dr. Abkowitz's research is hematopoietic stem cell (HSC) physiology. HSCs, the parent cells that establish and maintain blood cell production, reside in niches within marrow and are infrequent (< 1 per 105 marrow cells in mice, < 1 per 107 marrow cells in man). Their cell fate decisions are complex as they depend on microenvironmental as well as intracellular signals. Dr. Abkowitz's laboratory uses novel experimental techniques, including studies of mobilization and homing in parabiotic mice, to derive information about the number and behavior of murine HSCs in vivo. In addition, in collaboration with Dr. Peter Guttorp, Department of Statistics, she uses stochastic simulation and evolutionary analyses to estimate the mean rates of replication, differentiation, and apoptosis of HSCs in mouse, cat, non-human primate, and most recently, man. She is applying this approach to understand the mechanisms by which human HSCs reconstitute hematopoiesis after transplantation, the pathophysiology of clinical marrow failure syndromes, and the kinetics of cancer stem cell expansion.
Her second area of research emphasis is the molecular and cellular events that control red cell differentiation. Dr. Abkowitz identified, through expression cloning, a membrane transport protein (FLVCR) that is critical for the survival of early erythroid precursors (CFU-E/proerythroblasts) and demonstrated that it exports cytoplasmic heme. Heme is synthesized by all aerobic cells and is a critical component of cytochromes, catalases, glutathione peroxidase, hydroxylases, and nitric oxide synthase, as well as myoglobin and hemoglobin. It is also a transcriptional and translational regulator of globin synthesis (and thus erythropoiesis). However, excess free heme is toxic, leading to cell apoptosis, so that a tight balance between heme synthesis and heme use is required. Flvcr-/- mice die during embryogenesis due to a failure in definitive erythropoiesis and conditionally-deleted Flvcr flox/flox; Mx-cre mice develop red cell aplasia. It also appears that FLVCR is important in placenta, liver, duodenum, brain and macrophage, and may serve to protect these non-erythroid tissues from high intercellular heme flux and/or facilitate heme trafficking and systemic iron hemostasis. Dr. Abkowitz uses genetic and physiologic approaches to investigate the functions of FLVCR and its role as a modifier of disease phenotype. More broadly, she is interested in understanding the coordinate molecular regulation of heme and globin synthesis as primary erythroid progenitor cells mature, and how dyscoordination might lead to ineffective erythropoiesis in MDS and other disorders.