Advances in JAK2 inhibitors for treatment of myeloproliferative neoplasms / 药学学报

Myeloproliferative neoplasms (MPNs) result from clonal expansion of haematopoietic stem cells and are characterized by abnormal proliferation of myeloid lineage cells in the bone marrow. Sustained activation of JAK-STAT signaling pathway due to JAK2 phosphorylation is an important cause of MPNs, and mutation of JAK2 kinase can keep it in a state of continuous phosphorylation. The most typical mutation in JAK2 is a site mutation of V617F in the pseudokinase domain. The JAK2V617F-activating mutation is highly prevalent in MPNs, with frequencies estimated at approximately 95% in polycythaemia vera (PV) and 50% in primary myelofibrosis (PMF) and essential thrombocytosis (ET) patients. It is now clear that JAK2 is an important target for treatment of MPNs. Inhibiting aberrant activation of the JAK2-STAT signaling pathway has become a popular trend in research for effective treatment of MPNs. This review summarizes the research progress in developing JAK2 inhibitors for treatment of MPNs in recent years, including the new discoveries of the biological functions of JAK2, the relationship between JAK2 and MPN, and the status of development of JAK2 small molecule inhibitors.

Clinical significances of JAK2 mutation in patients with polycythemia vera / 中国肿瘤临床

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by overproduction of red blood cells. The pathogenesis of PV is not completely understood. However, studies report that it may be associated with the gain-of-function somatic mutation of JAK2 and that the JAK2 mutation provides a molecular diagnostic standard for PV. JAK2 mutation and allele mutation bur-den are useful for predicting clinical features and courses. The discovery of JAK2 mutation has promoted the development of molecu-lar-targeted therapy, such as the JAK2 inhibitor, ruxolitinib, a drug with superior therapeutic effect and safety that is used in clinical practice. The JAK2 allele mutation burden is closely associated with leukocytosis and progression to myelofibrosis (MF). A high JAK2 al-lele mutation burden may be a risk factor for poor prognosis. This article briefly reviews the clinical significance of the JAK2 mutation in patients with PV.

Progress of molecular pathogenesis and treatment in polycythemia vera / 白血病·淋巴瘤

Polycythemia vera (PV) is a chronic clonal myeloproliferative disorder of hematopoietic stem cell characterized by a pronounced symptom burden, including fatigue, pruritus, and symptomatic splenomegaly, along with an increased risk of thrombosis and the potential for evolution to myelofibrosis (MF) and secondary acute myeloid leukemia. Research on pathogenesis, diagnosis and treatment of PV has made a great progress since the discovery of JAK2 V617F mutation in 2005. The change of epigenetics plays an important role in the progression of PV, and the drugs for apparent genetic alteration may improve the life quality of PV patients.