Approximates 80% of essential thrombocythemia (ET) patients carrying JAK2, CALR, MPL mutations. However, there is still 20% of ET patients are negative for all three mutations. Our previous studies have demonstrated that platelet-derived growth factor (PDGF) and its receptor (PDGFR) has a potential effect in the regulation of hematopoiesis and megakaryopoiesis. Therefore, we speculated that PDGF/PDGFR may plays an important role in megakaryocyte/platelet related disease, such as ET. In this study, we found an increase of PDGF-BB and PDGFR expression in ET patients comparing to the normal persons. We then used the adjusted dosage of PDGF-BB (1.5ug/kg/d) to establish an ET mimic mouse model. We found that PDGF-BB can enhance platelet production in vivo significantly, while PDGFR inhibitor imatinib can block this effect. Bone marrow histology data also confirmed the megakaryopoiesis effect of PDGF, as shown by an increased number of megakaryocytes in PDGF-treated mouse. The addition of imatinib can block the effect, evident by a decrease number of megakaryocytes and an increase of apoptosis. Furthermore, we demonstrated that PDGF-BB activated theP-JAK2, the P-STAT3 and the P-AKT expression in the megakaryocytic cell line CHRF-288, while addition of imatinib can reduce the phosphorylation level of all three genes. Our results suggested that the overexpression of PDGF-BB and PDGFR may be important in the pathogenesis of ET, especially in the JAK2-mutation negative ET. The elevated PDGF-BB activates PDGFR with subsequently activation of the JAK2/ STAT3 and PI3K/AKT pathway. Imatinib may have an effect on treating ET via blocking PDGFR and the following JAK2/STAT3 and PI3K/AKT pathway. This study suggests that PDGF/PDGFR may be involved in the pathogenesis of essential thrombocythemia, and the expression of PDGF-BB and PDGFR is potential to be a diagnostic index of ET. Blockage of PDGFR by imatinib may be a new therapeutic target for ET.

Figure 1
Figure 1. Effect of PDGF-BB on Jak2/Stat3 and PI3K/Akt pathway of megakaryocytes.
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Effect of PDGF-BB on Jak2/Stat3 and PI3K/Akt pathway of megakaryocytes.

Figure 1
Figure 1. Effect of PDGF-BB on Jak2/Stat3 and PI3K/Akt pathway of megakaryocytes.
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Effect of PDGF-BB on Jak2/Stat3 and PI3K/Akt pathway of megakaryocytes.

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Figure 2
Figure 2. The platelet numbers and the megakaryocytes of each group mice.
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The platelet numbers and the megakaryocytes of each group mice.

Figure 2
Figure 2. The platelet numbers and the megakaryocytes of each group mice.
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The platelet numbers and the megakaryocytes of each group mice.

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Figure 3
Figure 3. Potential mechanisms for imatinib in treating essential thrombocythemia.
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Potential mechanisms for imatinib in treating essential thrombocythemia.

Figure 3
Figure 3. Potential mechanisms for imatinib in treating essential thrombocythemia.
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Potential mechanisms for imatinib in treating essential thrombocythemia.

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Disclosures

No relevant conflicts of interest to declare.

Topics:
imatinib mesylate, platelet-derived growth factor receptor, thrombocythemia, hemorrhagic, platelet-derived growth factor, stat3 protein, 1-phosphatidylinositol 3-kinase, proto-oncogene proteins c-akt, platelet count measurement, megakaryocytes, mice

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2016 by The American Society of Hematology
2016
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