Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage.
The JAK2 V617F mutation, present in the majority of polycythemia vera (PV) patients, causes constitutive activation of JAK2 and seems to be responsible for the PV phenotype. However, the transcriptional changes triggered by the mutation have not yet been totally characterized. In this study, we performed a large-scale gene expression study using serial analysis of gene expression in bone marrow cells of a newly diagnosed PV patient harboring the JAK2 V617F mutation and in normal bone marrow cells of healthy donors. JUNB was one of the genes upregulated in PV, and we confirmed, by quantitative real-time PCR, an overexpression of JUNB in hematopoietic cells of other JAK2 V617F PV patients. Using Ba/F3-EPOR cell lines and primary human erythroblast cultures, we found that JUNB was transcriptionally induced after erythropoietin addition and that JAK2 V617F constitutively induced JunB protein expression. Furthermore, JUNB knockdown reduced not only the growth of Ba/F3 cells by inducing apoptosis, but also the clonogenic and proliferative potential of human erythroid progenitors. These results establish a role for JunB in normal erythropoiesis and indicate that JunB may play a major role in the development of JAK2 V617F myeloproliferative disorders.
Hematology and Hemotherapy Center, State University of Campinas, Campinas, São Paulo, Brazil.
B
B
da Costa Reis Monte-Mór
I
I
Plo
A F
AF
da Cunha
G G L
GG
Costa
D M
DM
de Albuquerque
A
A
Jedidi
J-L
JL
Villeval
S
S
Badaoui
I
I
Lorand-Metze
K B B
KB
Pagnano
S T O
ST
Saad
W
W
Vainchenker
F F
FF
Costa
D001853:Bone Marrow / Q000473:pathology; D019070:Cell Lineage; D049109:Cell Proliferation; D004912:Erythrocytes / Q000473:pathology*; D004920:Erythropoiesis; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000209:etiology*; D011087:Polycythemia Vera / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured
D016755:Proto-Oncogene Proteins c-jun; D053614:Janus Kinase 2