title: Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms.
abstract: Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34(+) early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis.
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford Cancer Center, 875 Blake Wilbur Dr., Stanford, CA 94305-5821, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Oh
authors.forename: Erin F
authors.initials: EF
authors.lastname: Simonds
authors.forename: Carol
authors.initials: C
authors.lastname: Jones
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hale
authors.forename: Yury
authors.initials: Y
authors.lastname: Goltsev
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Gibbs
authors.forename: Jason D
authors.initials: JD
authors.lastname: Merker
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D018388:Codon, Terminator; D025461:Feedback, Physiological / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2 / Q000378:metabolism; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018388:Codon, Terminator; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2
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