Education and Training:

A.B., Harvard University, Cambridge, MA (1972)

M.D., Harvard Medical School, Boston, MA (1977)

Residency in Internal Medicine, Beth Israel Hospital, Boston, MA (1977- 80)

Fellowship in Hematology, University of Washington, Seattle, WA (1980-83)

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 physiology, monocyte trafficking

RESEARCH DESCRIPTION

One focus of Dr. Abkowitz’s research is hematopoietic stem cells (HSC). HSC, 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 HSC 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 HSC in mouse, cat, and non-human primate, and man.  Also, with competitive transplantation stuides of null and transgenic mice, she is determining the mechanisms by which HSC and progenitor cells clonally expand to dominate hematopoiesis in the myeloproliferative disorders.

The second area of research emphasis is the molecular and cellular events that control red cell differentiation. Recently, Dr. Abkowitz identified, through expression cloning, a membrane transport protein (FLVCR) that is critical for the survival of early erythroid precursors (CFU-E and proerythroblasts), and demonstrated that it exports cytoplasmic heme. Heme is a critical component of cytochromes, catalases, glutathione peroxidase, hydroxylases, and nitric oxide synthase, as well as myoglobin and hemoglobin, and is necessary for the survival and integrity of all aerobic cells. 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 neonatally 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. The laboratory is using genetic and physiologic approaches to investigate the functions of Flvcr and its role as a modifier of disease phenotype. Dr. Abkowitz is also 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.

SELECTED PUBLICATIONS

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.

Chen J, Larochelle A, Fricker S, Bridger G, Dunbar CE, Abkowitz JL:  Mobilization as a preparative regimen for hematopoietic stem cell transplantation. Blood 107:3764-3771, 2006.

Abkowitz 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.

Shepherd 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, Knoblaugh  S, 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. In press.