Abstract
Polycythaemia vera (PV) is a haematological disorder caused by an overproduction of erythroid cells. To date, the molecular mechanisms involved in the disease pathogenesis are still ambiguous. This study aims to identify aberrantly expressed proteins in erythroblasts of PV patients by utilizing mass spectrometry-based proteomic analysis. Haematopoietic stem cells (HSCs) were isolated from newly-diagnosed PV patients, PV patients who have received cytoreductive therapy, and healthy subjects. In vitro erythroblast expansion confirmed that the isolated HSCs recapitulated the disease phenotype as the number of erythroblasts from newly-diagnosed PV patients was significantly higher than those from the other groups. Proteomic comparison revealed 17 proteins that were differentially expressed in the erythroblasts from the newly-diagnosed PV patients compared to those from healthy subjects, but which were restored to normal levels in the patients who had received cytoreductive therapy. One of these proteins was S-methyl-5′-thioadenosine phosphorylase (MTAP), which had reduced expression in PV patients’ erythroblasts. Furthermore, MTAP knockdown in normal erythroblasts was shown to enhance their proliferative capacity. Together, this study identifies differentially expressed proteins in erythroblasts of healthy subjects and those of PV patients, indicating that an alteration of protein expression in erythroblasts may be crucial to the pathology of PV.
Highlights
Polycythaemia vera (PV) is a haematological disorder caused by an overproduction of erythroid cells
In vitro culture of erythroid cells differentiated from Haematopoietic stem cells (HSCs) of newly-diagnosed PV patients showed a significantly higher rate of expansion of early erythroblasts compared to those of treated PV patients and controls, recapitulating the major disease phenotype of PV, which is an overproduction of RBCs2
It could be conceivably assumed that prior cytoreductive treatment may affect HSCs of PV patients, resulting in decreased cell numbers observed in PVT
Summary
Polycythaemia vera (PV) is a haematological disorder caused by an overproduction of erythroid cells. Proteomic comparison revealed 17 proteins that were differentially expressed in the erythroblasts from the newly-diagnosed PV patients compared to those from healthy subjects, but which were restored to normal levels in the patients who had received cytoreductive therapy. One of these proteins was S-methyl-5′-thioadenosine phosphorylase (MTAP), which had reduced expression in PV patients’ erythroblasts. A proteomic analysis of granulocytes from PV patients using twodimensional gel electrophoresis showed differential expression of 65 proteins in granulocytes from PV patients[12] Another proteomic study adopted mass spectrometry for systematic evaluation of JAK2V617F mutation effects in the murine Ba/F3 cell line, identifying over 5000 proteins that were associated with the JAK2V617F mutation. A number of proteins have been shown to have abnormal expression patterns in PV patients, the molecular mechanisms that contribute to the pathological characteristics of PV are still unclear
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