CURRENT CLINICAL INTERESTS
General hematology; myelodysplastic and myeloproliferative disorders, pure red cell aplasia, aplastic anemia and other marrow failure syndromes
CURRENT RESEARCH INTERESTS
Hematopoietic stem cells, erythropoiesis, heme biology,
pathophysiology and therapy of marrow failure
A major focus of Dr. Abkowitz’s research is understanding 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 (and other proteins). As heme synthesis begins with succinyl coA (a TCA cycle intermediate) and glycine (an amino acid), it links metabolism to cell fate decisions. However, excess free heme is toxic, leading to cell apoptosis, so that a tight balance between heme synthesis and heme use is required, especially in erythroid precursors, where the need for heme for hemoglobin is high and there is rapid cell expansion and differentiation. 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 (and heme export) 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 studies the coordinate molecular regulation of heme and globin synthesis as erythroid progenitor cells mature, and how poor coordination leads to ineffective erythropoiesis in MDS and other macrocytic anemias.
Her second area of research emphasis 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 104 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.
Lastly, she, with Drs. Sioban Keel (Medicine/Hematology), Akiko Shimamura (Pediatric Hematology/oncology) and Mary-Claire King (Medical genetics and Genome sciences), are identifying novel genes associated with marrow failure by exome sequencing of members of families with cytopenia and are functionally validating their physiology. She also studies genotype:phenotype relationships in congenital marrow failure.
Abkowitz JL, Catlin SN, Guttorp P: Evidence that hematopoiesis may be stochastic in vivo. Nature Medicine 2:190-197, 1996.
Abkowitz JL, Persik MT, Shelton GH, Catlin SN,
Guttorp P, Kiklevich JV: An X-chromosome gene regulates
hematopoietic stem cell kinetics. Proc. Natl. Acad. Sci. USA 95:3862-3866, 1998.
Kennedy DW, Abkowitz JL: Mature monocytic cells enter tissues and engraft.
Proc. Natl. Acad. Sci. USA 95:14944-14949, 1998.
Quigley JG, Yang Z, Worthington MT, Phillips JD,
Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL:
Identification of a human heme exporter that is essential for
erythropoiesis. Cell 118:757-766, 2004.
J, Larochelle A, Fricker S, Bridger G,
CE, Abkowitz JL: Mobilization as a preparative regimen
for hematopoietic stem cell transplantation. Blood
JL, Chen J: Studies of c-Mpl function distinguish the replication
of hematopoietic stem cells from the expansion of differentiating
clones. Blood 109:5186-5190, 2007.
BE, Kiem HP, Lansdorp PM, Dunbar CE, Aubert G, LaRochelle A, Seggewiss
R, Guttorp P, Abkowitz JL: Hematopoietic stem cell
behavior in non-human primates. Blood 110:1806-1813, 2007.
Keel SB, Doty RT, Yang Z, Quigley JG, Chen J,
Kingsley PD, De Domenico I, Vaughn MB,
Kaplan J, Palis
J, Abkowitz JL:
A heme export protein is required for red blood cell differentiation
and iron homeostasis. Science 319:825-828, 2008.
Keel SB, Abkowitz
JL: The microcytic red
cell and the anemia of inflammation. N. Engl. J. Med.
Yang Z, Phillips JD,
Doty RT, Giraudi P, Ostrow JD, Tiribelli C, Smith A, Abkowitz JL: Kinetics
and specificity of FLVCR export function and its dependence of
hemopexin. J. Biol. Chem. 285:28874-28882, 2010.
Catlin SN, Busque L, Gale R, Guttorp P, and Abkowitz
JL: The replication rate of human hematopoietic stem cells in vivo. Blood
Hromas R, Abkowitz
JL, and Keating A: Facing the NIH funding crisis: how professional societies can help. JAMA