Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice.
The Jak2(V617F) mutation is found in most classical BCR/ABL-negative myeloproliferative neoplasms (MPNs). Usually, heterozygosity of the mutation is associated with essential thrombocythemia (ET) and homozygosity with polycythemia vera (PV). Retrovirally transduced or transgenic animal models have shown that the mutation is sufficient for MPN development but that the level of expression is crucial for MPN phenotypes. Therefore we investigated the effect of an endogenous heterozygous expression of Jak2(V617F) in knock-in (KI) mice. These animals displayed constitutive JAK2 activation and autonomous erythroid progenitor cell growth. Mice suffered from marked polycythemia, granulocytosis and thrombocytosis. Spleens and marrows displayed myeloid trilineage hyperplasia. Most animals survived to develop advanced fibrosis in these organs at around 9 months of age. In conclusion, constitutive heterozygous expression of JAK2(V617F) in mice is not embryo-lethal but results in severe PV-like disease with secondary myelofibrosis and not in ET-like disease as expected from patient study.
Marty
Caroline
C
Inserm U1009, Institut Gustave Roussy, PR1, 114 rue Edouard Vaillant, 94805 Villejuif, France.
Lacout
Catherine
C
Martin
Antoine
A
Hasan
Salma
S
Jacquot
Sylvie
S
Birling
Marie-Christine
MC
Vainchenker
William
W
Villeval
Jean-Luc
JL
D019943:Amino Acid Substitution; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D019070:Cell Lineage; D003433:Crosses, Genetic; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D017354:Point Mutation; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D013154:Spleen / Q000473:pathology; D013920:Thrombocythemia, Essential / Q000201:enzymology / Q000235:genetics
C507924:JAK2 protein, human; D053614:Janus Kinase 2