title: JAK and MPL mutations in myeloid malignancies.
abstract: The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D053616:Janus Kinase 3 / Q000235:genetics*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D050791:STAT Transcription Factors; D015398:Signal Transduction
chemical_list: D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; C082218:MPL protein, human; D053614:Janus Kinase 2; D053616:Janus Kinase 3