Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms

Blood. 2010 Aug 12;116(6):988-92. doi: 10.1182/blood-2010-02-270108. Epub 2010 Apr 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Division / physiology
  • Cell Line, Tumor
  • Codon, Terminator
  • Feedback, Physiological / physiology
  • Gene Deletion
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 2 / metabolism
  • Mutation, Missense
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / metabolism*
  • Proteins / genetics*
  • Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / physiology*

Substances

  • Codon, Terminator
  • Intracellular Signaling Peptides and Proteins
  • LNK protein, human
  • Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • JAK2 protein, human
  • Janus Kinase 2