Fms-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) (FLT3/JAK2)

Fms-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) are essential tyrosine kinases that regulate the proliferation, differentiation, and survival of hematopoietic stem and progenitor cells [12, 14]. FLT3 is a class III receptor tyrosine kinase that, upon activation, triggers the PI3K/AKT and RAS/MAPK pathways to promote cell growth [19]. JAK2 is a non-receptor tyrosine kinase that mediates signaling from various cytokine receptors through the JAK-STAT pathway, playing a central role in normal hematopoiesis [20, 21]. Mutations in these proteins, such as FLT3 internal tandem duplications (FLT3-ITD) and the JAK2 V617F mutation, lead to constitutive signaling that drives the pathogenesis of acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs) like myelofibrosis [11, 13, 16]. Dual inhibition of FLT3 and JAK2 is a therapeutic strategy designed to block redundant or compensatory signaling pathways that contribute to disease progression and resistance to single-agent therapies [7, 10]. Drugs like pacritinib target both kinases to reduce tumor burden and alleviate symptoms such as splenomegaly, particularly in patients with severe cytopenias who may not tolerate broader kinase inhibition [1, 3, 5].

Other names

CD135FLK2STK1Fms-related tyrosine kinase 3Janus kinase 2JAK-2JAK2V617F

Dual inhibition of the ATP-binding sites of the FLT3 and JAK2 kinase domains, which prevents autophosphorylation and blocks downstream signaling through the STAT5, PI3K/AKT, and RAS/MAPK pathways [1, 3, 7]. This combined inhibition targets both the primary drivers of myeloid proliferation and compensatory signaling pathways that contribute to drug resistance [7, 10].