Dasatinib inhibits progenitor cell proliferation from polycythaemia vera.
BACKGROUND
A mutation of Janus kinase 2 V617F is present in most patients with polycythaemia vera (PV). However, it is generally believed that JAK2(V617F) is not the sole molecular abnormality in PV. Since dasatinib is currently evaluated in patients with PV, it is of interest to study the effects of dasatinib on the growth of clonal progenitor cells in vitro.


METHODS
Peripheral blood mononuclear cells from patients with PV, chronic myeloid leukaemia (CML) and controls were exposed to dasatinib (0.1 to 500 nm mL(-1)). Colony growth was stimulated by interleukin-3, granulocyte-macrophage colony-stimulating factor and erythropoietin. Endogenous erythroid colony (EEC) growth was investigated without exogenous cytokines. Real-time PCR was performed to assess the percentage of JAK2(V617F) cells.


RESULTS
10 nm of dasatinib suppressed EEC growth from PV by 89% (P = 0.002). This inhibition was dose dependent and occurred at pharmacological concentrations. Erythroid and myeloid colony growth was also significantly suppressed in the presence of exogenous cytokines. When compared to PV the inhibition of stimulated colony growth was significantly less pronounced in controls but tended to be more vigorous in CML. Interestingly, despite the potent inhibition of PV cells real-time PCR revealed that the numbers of JAK2(V617F) transcripts did not decrease upon exposure to dasatinib.


CONCLUSIONS
This study shows a marked inhibition of the proliferative capacity of progenitor cells from PV. Although JAK2(V617F) transcript levels did not decrease upon exposure to dasatinib, the drug might suppress PV progenitors through inhibition of a yet undefined molecular target.
Wappl
M
M
Medical University of Vienna, Austria.
Jaeger
E
E
Streubel
B
B
Gisslinger
H
H
Schwarzinger
I
I
Valent
P
P
Oehler
L
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000473:pathology; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000473:pathology; D011087:Polycythemia Vera / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D053614:Janus Kinase 2; D000069439:Dasatinib