[The activation of JAK/STAT signal pathway in hypereosinophilic syndrome and the patients therapeutic response to imatinib].
OBJECTIVE
To determine whether JAK/STAT pathway is involved in proliferation of hypereosinophilic syndrome (HES) cells, and reveal the pathogenesis of HES; observe the dynamic change of the clinical phenotype and hematological response, the expression of janaus kinase/signal transducer and activator of transcription (JAK/STAT) protein or FIP1L1-PDGFRA mRNA in one HES patient treated with low-dose imatinib.


METHODS
The granulocytes of peripheral blood of 4 HES patients, including 3 FIP1L1-PDGFRA positive cases and 1 negative case, were collected. The expression of JAK2, STAT3, and phosphorylated STAT (P-STAT5) proteins were detected by western blotting. One FIP1L1-PDGFRA fusion gene positive patient was administered with low-dose imatinib. Retrospective reverse transcription polymerase chain reaction (RT-PCR) analysis of FIP1L1-PDGFRA was performed and the expressions of JAK2, STAT3 and P-STAT5 were detected by western blotting before treatment and 10, 30, and 60 days after the beginning of treatment.


RESULTS
Upregulation of JAK2, STAT3, and P-STAT5 proteins was shown in 3 FIP1L1-PDGFRA fusion gene positive HES patients, while all of these proteins were not expressed in one case of FIP1L1-PDGFRA negative HES. Continuous hematological remission was observed in one FIP1L1-PDGFRA fusion gene positive HES patient after low-dose imatinib treatment. The amount of FIP1L1-PDGFRA transcripts in peripheral blood granulocytes was significantly decreased in 30 days after therapy and turned negative 60 days after therapy. JAK2, STAT3, STAT5, and P-STAT5 expressions were all down-regulated time-dependently and were all negative 60 days after.


CONCLUSIONS
There is excessive activation of JAK/STAT signal pathway in HES patient, which may contribute to the malignant proliferation of eosinophils. Low-dose imatinib, that induces complete hematological and molecular genetic remission, exerts significant effects on FIP1L1-PDGFRA positive HES.
Li
Bin
B
Division of Hematology, Institute of Molecular Hematology, the Second Xiangya Hospital, Central South University, Changsha 410011, China.
Zhang
Guang-Sen
GS
Dai
Chong-Wen
CW
Pei
Min-Fei
MF
D000328:Adult; D001549:Benzamides; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000068877:Imatinib Mesylate; D053613:Janus Kinase 1; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism
D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; C507904:JAK1 protein, human; D053613:Janus Kinase 1