Advances in understanding the pathogenesis of primary familial and congenital polycythaemia

Abstract

Primary familial and congenital polycythemia (PFCP) is an autosomal-dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signalling. We focus on recent studies describing mechanisms underlying Epo-dependent EpoR down-regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP.

Figure 1

Signaling from the EpoR. A. Proteins recruited to EpoR cytoplasmic tyrosine residues that positively or negatively regulate EpoR signaling are depicted. B. Truncated EpoR from PFCP patients lack parts of the EpoR cytoplasmic domain. Y401 is retained in some but not all of the PFCP receptors.

Figure 1

Signaling from the EpoR. A. Proteins recruited to EpoR cytoplasmic tyrosine residues that positively or negatively regulate EpoR signaling are depicted. B. Truncated EpoR from PFCP patients lack parts of the EpoR cytoplasmic domain. Y401 is retained in some but not all of the PFCP receptors.

Figure 2

Epo-induced EpoR down-regulation. Upon Epo stimulation, EpoR is down-regulated through two mechanisms, one dependent on p85 and the other on β-TrCP-mediated proteasomal degradation.