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
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.
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
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
Abkowitz JL, Catlin SN, Guttorp P:
Evidence that hematopoiesis may be stochastic in vivo. Nature Medicine
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.
Fong Y, Guttorp P, Abkowitz
JL: Bayesian inference
and model choice in a hidden stochastic two-compartment model of
hematopoietic stem cell fate decisions. Ann Appl Statistics
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.