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The somatic activating janus kinase 2 mutation (JAK2)^V617F is detectable in most patients with polycythemia vera (PV). Here we report that CP-690550 exerts greater antiproliferative and pro-apoptotic activity against cells harboring JAK2^V617F compared with JAK2^WT. CP-690550 treatment of murine factor-dependent cell Patersen–erythropoietin receptor (FDCP-EpoR) cells harboring human wild-type or V617F JAK2 resulted in inhibition of cell proliferation with a 50% inhibitory concentration (IC₅₀) of 2.1 µM and 0.25 µM, respectively. Moreover, CP-690550 induced a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2^V617F, whereas a lesser effect was observed for cells carrying wild-type JAK2. This activity was coupled with inhibition of phosphorylation of the key JAK2^V617F-dependent downstream signaling effectors signal transducer and activator of transcription (STAT)3, STAT5, and v-akt murine thymoma viral oncogene homolog (AKT). Furthermore, CP-690550 treatment of ex-vivo-expanded erythroid progenitors from JAK2^V617F-positive PV patients resulted in specific, antiproliferative (IC₅₀ = 0.2 µM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls were less sensitive to CP-690550 in proliferation (IC₅₀ > 1.0 µM), and apoptosis assays. The antiproliferative effect on expanded patient progenitors was paralleled by a decrease in JAK2^V617F mutant allele frequency, particularly in a patient homozygous for JAK2^V617F. Flow cytometric analysis of expanded PV progenitor cells treated with CP-690550 suggests a possible transition towards a pattern of erythroid differentiation resembling expanded cells from normal healthy controls. (Cancer Sci 2008; 99: 1265–1273)