Version:1.0 StartHTML:0000000207 EndHTML:0000006199 StartFragment:0000002599 EndFragment:0000006163 SourceURL:file://localhost/Users/mohim/Desktop/ASH%202011/Dongqing%20Yan%202011%20ASH%20Abstract.doc
The JAK2V617F mutation has been identified in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of multiple signaling molecules/pathways. However, the key signaling downstream of JAK2V617F required for transformation, induction and maintenance of MPNs remains elusive. Using a mouse genetic strategy, we found that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas inducible expression of Jak2V617F in mice resulted in all the features of human PV, including increase in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knock-in mice normalized all the blood parameters and the spleen size. Histopathologic analyses revealed that Stat5 deficiency blocked the development of PV in mice expressing Jak2V617F. In addition, deletion of Stat5 completely abrogated erythropoietin (Epo)-independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Flow cytometric analysis revealed that concomitant deletion of Stat5 reduced the Jak2V617F-induced expansion of LSK (lin−Sca-1+c-kit+) and MEP (megakaryocyte-erythroid progenitors) as well as CD71+Ter119+ and Gr-1+Mac-1+ populations to normal levels. Unlike Jak2V617F knock-in mice, which developed myelofibrosis at old age, Stat5-deficient Jak2V617F-expressing mice failed to develop myelofibrosis. Re-expression of Stat5 in Stat5-deficient Jak2V617F knock-in mice bone marrow by retroviral transduction completely rescued the defects in transformation of hematopoietic progenitors and the PV phenotype. Furthermore, deletion of Stat5 after establishment of PV disease in the transplanted animals expressing Jak2V617F by injection with polyinosine:polycytosine (pI:pC) normalized the blood parameters and inhibited the progression of the disease. Together, these results indicate a critical function for Stat5 in the induction and maintenance of PV. Biochemical analyses revealed that Stat5 deficiency significantly inhibited constitutive phosphorylation of p70S6 kinase and markedly reduced expression of Bcl-xL, Cyclin-D2 and Pim-1 mediated by Jak2V617F. These suggest that p70S6 kinase, Bcl-xL, Cyclin-D2 and Pim-1 are downstream targets of Jak2V617F-Stat5 signaling, and they may play a role in hematopoietic transformation induced by Jak2V617F. These findings provide strong support for the development of Stat5 inhibitors as targeted therapies for the treatment of PV and other JAK2V617F-positive MPNs.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.