Imatinib effect on growth and signal transduction in polycythemia vera.
OBJECTIVE
An activating mutation of Janus kinase 2 (JAK2) in majority of polycythemia vera (PV) and other myeloproliferative disorders was reported. As imatinib inhibits several tyrosine kinases, we studied its effect in PV.


METHODS
We employed FDCP reporter cells expressing wild-type JAK2 and mutant JAK2(V617F) to study the efficacy of imatinib by cell proliferation assay and its effect on several cell-signaling events. Imatinib's efficacy was also examined on in vitro expanded native human erythroid progenitors. In addition, analysis of the percent JAK2 T-allele and phospho-signal transducer and activator of transcription-5 (STAT5) in granulocytes of PV patients following imatinib therapy was assessed.


RESULTS
Imatinib showed a specific time- and dose-dependent growth inhibitory effect on FDCP cells expressing JAK2(V617F), wherein we observed imatinib's inactivation of JAK2, STAT5 and cKIT proteins. In vitro expanded human PV erythroid progenitors were more sensitive to imatinib than normal erythroid progenitors and FDCP cells expressing JAK2(V617F), with growth inhibition at concentrations attainable in vivo. In an ongoing clinical study, a PV patient showed strong correlation between the percent JAK2 T-allele and his responsiveness to imatinib therapy.


CONCLUSIONS
Our data elucidate the therapeutic benefit of imatinib seen in some PV patients. Our data suggest that JAK2/STAT5 and cKIT activation may be integrated. To our knowledge, this is the first report demonstrating imatinib's effect on PV erythroid progenitors. These studies underscore the limitation of experiments using cell lines expressing the gene of interest.
Gaikwad
Amos
A
Department of Pediatric-Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA.
Verstovsek
Srdan
S
Yoon
Donghoon
D
Chang
Ko-Tung
KT
Manshouri
Taghi
T
Nussenzveig
Roberto
R
Cortes
Jorge
J
Vainchenker
William
W
Prchal
Josef T
JT
D000483:Alleles; D001549:Benzamides; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism* / Q000473:pathology; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011087:Polycythemia Vera / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C507924:JAK2 protein, human; D053614:Janus Kinase 2