Molecular genetic alterations

amounts of C-MPL protein when assessed with an antibody to the C-terminal (cytoplasmic) end of the protein. Using an antibody to the N-terminal end, Moliterno and Spivak (1999) demonstrated the presence, at a reduced level, of two isoforms of C-MPL in PV platelets. One isoform represented normal C-MPL and the other was the result of defective C-MPL glycosylation. Platelets from patients with reduced C-MPL expression failed to show the appropriate protein tyrosine phosphorylation in response to TPO, indicating a defect in C-MPL signaling. In ET, reduced amounts of C-MPL protein and mRNA have been demonstrated in the platelets of some but not all patients. However, results are inconsistent between groups, possibly because of different sources of antibodies or pathogenetic heterogeneity. Despite this, decreased C-MPL expression within bone marrow megakaryocytes may help distinguish some PV and ET patients from patients with reactive conditions.

Given the lack of mutations in acquired MPDs in EPO and TPO and their receptors, attention turned to other growth factors that may play a role in MPD. TGF-P1 is a strong negative regulator of early hemopoietic stem cells and, in particular, plays an important role in the regulation of megakaryopoi-esis. TGF-P1 is itself largely produced by megakaryocytes and platelets, and negatively regulates megakaryopoiesis. Within the bone marrow, TGF-P1 stimulates the production of TPO, which in turn induces the expression of TGF-PRI and TGF-PRII by megakaryocyte progenitors. This renders them susceptible to the inhibitory effects of TGF-P1, completing the negative feedback loop. Megakaryocyte progenitors from ET patients show reduced sensitivity to the inhibitory effects of TGF-P1, which may in part be responsible for the increased rate of platelet production. One possible mechanism for this effect is reduced activity of TGF-PRII. Expression of TGF-PRII is decreased in CD34+ cells from IMF patients and in neutrophils from PV, ET and CML patients. Acquired mutations are present in many solid tumors, leading to a truncated protein that lacks the kinase domain and is insensitive to the effect of TGF-P1. No acquired mutations of TGF-PRII have been detected in PV or ET patients and methylation of the promoter and CpG island has been ruled out as a mechanism for reduced expression, at least for PV. Further studies of the TGF-P1 pathway in MPD are warranted.

Transcript levels of a novel cell surface receptor termed PRV-1 (also termed NB1 and CD177) are increased in granulocytes from most PV patients and in a significant number of ET patients. In normal individuals, PRV-1 mRNA is expressed in bone marrow cells but its level is reduced in differentiated neutrophils. The PRV-1 protein is a member of the uPAR/ CD59/Ly6 family, a group of cell membrane proteins attached to the extracellular membrane by a lipid anchor. These proteins play a role in signal transduction including, but not exclusively, activation of the JAK/STAT pathway, although the specific function of PRV-1 is not known. Despite the significant increase in PRV-1 mRNA levels in PV granulocytes, levels of the cell surface protein are not significantly different between patients and normal individuals. Detection of increased PRV-1 transcript levels in granulocytes by quantitative RT-PCR appears to discriminate patients with PV from normal individuals and those with reactive erythrocytosis. No structural alterations of the PRV-1 gene have been observed in MPD patients, suggesting that PRV-1 overexpression is likely to be a secondary consequence of the acquired genetic defect that causes PV.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment