Real-time bioluminescence imaging of polycythemia vera development in mice.
Polycythemia vera (PV) is a myeloproliferative disorder involving hematopoietic stem cells. A recurrent somatic missense mutation in JAK2 (JAK2V617F) is thought to play a causal role in PV. Therefore, targeting Jak2 will likely provide a molecular mechanism-based therapy for PV. To facilitate the development of such new and specific therapeutics, a suitable and well-characterized preclinical animal model is essential. Although several mouse models of PV have been reported, the spatiotemporal kinetics of PV formation and progression has not been studied. To address this, we created a bone marrow transplant mouse model that co-expresses mutant Jak2 and luciferase 2 (Luc2) genes. Bioluminescent imaging (BLI) was used to visualize disease cells and analyze the kinetics of PV development in vivo. To better understand the molecular mechanism of PV, we generated mice carrying a kinase inactive mutant Jak2 (Jak2K882E), demonstrating that the PV disease was dependent on constitutive activation of the Jak2 kinase activity. We further showed that the Jak2V617F mutation caused increased stem cell renewal activity and impaired cell differentiation, which was at least in part due to deregulated transcriptional programming. The Jak2V617F-Luc2 PV mice will be a useful preclinical model to characterize novel JAK2 inhibitors for the treatment of PV.
Ma
Yanhong
Y
Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Zhao
Shuxia
S
Zhu
Joe
J
Bettano
Kimberly A
KA
Qu
Xianlu
X
Marshall
C Gary
CG
Young
Jonathan R
JR
Kohl
Nancy E
NE
Scott
Martin L
ML
Zhang
Weisheng
W
Wang
Yuxun
Y
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis* / Q000235:genetics; D008163:Luminescent Measurements; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D011087:Polycythemia Vera / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D013234:Stem Cells / Q000201:enzymology / Q000473:pathology
D004791:Enzyme Inhibitors; D008156:Luciferases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2