Splenectomy normalizes hematocrit in murine polycythemia vera.
Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.
Department of Oncology-Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
Jan-Rung
JR
Mo
Anjili
A
Mathur
Minilik
M
Angagaw
Shuxia
S
Zhao
Yuxun
Y
Wang
Diana
D
Gargano
Alessandra
A
DiBacco
Eric S
ES
Bachman
D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004921:Erythropoietin / Q000378:metabolism; D006400:Hematocrit; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D011087:Polycythemia Vera / Q000097:blood* / Q000601:surgery*; D013154:Spleen / Q000378:metabolism; D013156:Splenectomy / Q000379:methods*
D004921:Erythropoietin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2