Basic sciences of the myeloproliferative diseases: pathogenic mechanisms of ET and PV.

The molecular pathogenesis of ET and PV is unknown, although the relatively indolent clinical course observed in most patients suggests that the defect may be subtle and difficult to establish. Clonality analysis using X-chromosome inactivation patterns in females on purified CD34+ cells have confirmed that a defect is present in the hematopoietic stem cell. However, at least in ET, a significant proportion of patients have polyclonal hemopoiesis, and this presumably reflects the heterogeneous nature of the disorder(s). Attention has focussed on the potential disruption of the physiological regulators EPO and TPO and their respective receptors. In familial disorders, pathological mutations have been identified in some, but by no means all, cases: EPO receptor mutations in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in CAMT. Equivalent ligand or receptor mutations have not been detected in ET or PV patients. However, there is evidence to suggest that c-mpl expression may be dysregulated, with low or absent c-mpl mRNA or protein reported in ET and/or PV patients. At present it is not clear whether this is the cause or consequence of the paradoxically normal/increased TPO levels found with both primary and secondary thrombocytosis. In vitro culture analysis has demonstrated both cytokine independence and hyper-sensitivity as a generalised feature of progenitor cells from many patients, but differences exist depending on the assays used and there is little understanding of the mechanism(s) underlying these responses. Two genes have recently been identified with increased mRNA expression in PV granulocytes: PRV-1, a novel cell surface receptor closely related to the uPAR/Ly6/CD59/snake toxin family of proteins, and NFI-B, a member of the nuclear factor I family which may be associated with TGF-beta resistance. Investigation of their regulation and biological effects may assist in determining the pathobiology of these elusive disorders.