Biology Reference
In-Depth Information
EPOR biology in hematological diseases
Polycythemia vera, myeloproliferative and myelodysplastic diseases,
erythroleukemia, Diamond-Blackfan anemia
Several studies focus on EPOR biology in hematological diseases in humans.
Although in mice, a point mutation in the extracellular or transmembrane
domain of EPOR results in a constitutively activation of the receptor, and dele-
tions in the intracellular domain increase EPO-mediated proliferation of ery-
throid progenitors [47, 80, 81] and result in erythroleukemia, several studies in
humans have failed to detect structural abnormalities of EPOR in poly-
cythemia vera and related myeloproliferative diseases as potential cause for
the increased sensitivity of cultured erythroid progenitors to recombinant EPO
(rEPO) [82-84]. There is no evidence that EPOR mutations are involved in
myelodysplasia, erythroleukemia, Diamond-Blackfan anemia, or pure red cell
aplasia [85, 86].
Idiopathic erythrocytosis
In idiopathic erythrocytosis, the red blood cell mass is increased without other
criteria of polycythemia vera. This disorder generally involves an autosomal
dominant mode of inheritance. It is defined by erythrocytosis without evolu-
tion into leukemia or myelodyplastic syndrome, absence of splenomegaly, nor-
mal white blood cell and platelet counts, low or moderate EPO plasma con-
centrations, normal P
50
, and hypersensitivity of erythroid progenitors to rEPO
in vitro
. Eight mutations in the cytoplasmic domain of EPOR have been iden-
tified in these patients [87-95]. They are clustered in a 122 bp region (between
nt5881 and nt6002, numbering according to [33]) in one copy of the gene and
result in the formation of a stop codon. Consequently, between 59 and 110
amino acids of the negative regulatory domain are lost. All deletions include
tyrosine 429 that acts as SHP-1 binding site (Fig. 1). The lack of JAK2
dephoshorylation by the negative regulatory loop of SHP-1 may result in
enhanced STAT5 activity and the pathomechanism for erythrocytosis. Other
pathomechanisms of idiopathic erythrocytosis may exist, particularly if asso-
ciated with high EPO plasma concentrations.
Biology of EPOR in non-hematopoietic tissues
Although the crucial role of EPO in hematopoiesis is known for decades, the
biology of EPO in non-hematopoietic tissues became evident first during the
last decade (Tab. 1). Experimental and first clinical data indicate the pharma-
cological potential of rEPO in various acute and chronic disorders. EPOR
expression in non-hematopoietic cells seems to be regulated in a developmen-
