Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2530-2532
Erythropoietin Receptor Mutations Associated With Familial
Erythrocytosis Cause Hypersensitivity to Erythropoietin in the
Heterozygous State
Stephanie S. Watowich,
Xiaoling Xie,
Ursula Klingmuller,
Juha Kere,
Mikael Lindlof,
Stig Berglund, and
Albert de la Chapelle
From the Department of Immunology, MD Anderson Cancer Center,
Houston, TX; Hans-Spemann-Laboratory, Max-Planck-Institute for
Immunobiology, Freiburg, Germany; the Department of Medical Genetics,
University of Helsinki, Helsinki, Finland; the Department of Medicine,
University of Lund, Malmo General Hospital, Malmo, Sweden; and Human
Cancer Genetics Program, James Cancer Hospital and Solove Research
Institute, and Comprehensive Cancer Center, Ohio State University,
Columbus, OH.
Inherited mutations in the erythropoietin receptor (EPOR) causing
premature termination of the receptor cytoplasmic region are associated
with dominant familial erythrocytosis (FE), a benign clinical condition
characterized by hypersensitivity of erythroid progenitor cells to EPO
and low serum EPO (S-EPO) levels. We describe a Swedish family with
dominant FE in which erythrocytosis segregates with a new truncation in
the negative control domain of the EPOR. We show that cells engineered
to concomitantly express the wild-type (WT) EPOR and mutant EPORs
associated with FE (FE EPORs) are hypersensitive to EPO-stimulated
proliferation and activation of Jak2 and Stat5. These results
demonstrate that FE is caused by hyperresponsiveness of
receptor-mediated signaling pathways and that this is dominant with
respect to WT EPOR signaling.
