Jak2-V617F Mouse

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a crucial role in the JAK/STAT signaling pathway, which transmits extracellular signals to the nucleus, promoting cell proliferation and division ^[1]. Myeloproliferative neoplasms (MPNs) are a group of hematological malignancies characterized by the continuous clonal proliferation of one or more relatively mature bone marrow cell lineages. Classic MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), all of which originate from the clonal expansion of a single hematopoietic stem cell with a somatic mutation, leading to single-lineage or multilineage hyperplasia ^[2]. The JAK2 V617F mutation is the most common pathogenic mutation in human MPNs. It results from a single nucleotide substitution of G to T at position 1849 in exon 14 of the JAK2 gene (c.1849G>T), causing a valine to phenylalanine substitution (p.V617F) ^[3]. This dominant gain-of-function (GOF) mutation affects the JH2 pseudokinase domain of JAK2, disrupting its autoinhibitory function, and leading to constitutive activation of JAK2 and the JAK/STAT pathway in the absence of a ligand. The JAK2 V617F mutation is detected in 50%-60% of ET and PMF patients and more than 95% of PV patients ^[4]. In PV, the mutation causes excessive red blood cell production, increasing blood viscosity and thrombotic risk. In ET, it leads to excessive platelet production, which also increases thrombotic risk. In PMF, it causes bone marrow fibrosis and abnormal blood cell production, leading to anemia, splenomegaly, and other complications ^[3-4].

The Jak2-V617F mice are generated by introducing a homologous mutation to the human JAK2 V617F into the mouse Jak2 gene via gene editing. This strain is homozygous lethal. Heterozygous Jak2-V617F mice exhibit classic MPN-like disease phenotypes such as splenomegaly and structural damage, significantly elevated red blood cell count, hemoglobin, hematocrit, white blood cell count, platelet count, marked megakaryocytic hyperplasia (with granulocytic and erythroid hyperplasia), extramedullary hematopoiesis, and congestion of splenic sinusoids. Therefore, Jak2-V617F mice can be used for studying the mechanisms of myeloproliferative neoplasms (MPNs) like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as for evaluating therapeutic drugs.