Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms
Year: 2010
Type: article
Study design: Case Report
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.
Source: Blood
Institutions: Stanford Medicine, Stanford University
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: In Vivo Cellular and Molecular Imaging Center@Stanford, Training Program in Investigative Hematology, G3161846315, Software & Hardware Inference Engines for Automated Determination of Primary Cell, Clinical and Laboratory Studies of Malignant Lymphomas, G7063900871, G8238088159, G8343853698, G9000055070, G9000095646, Understanding Influenza and SARS-CoV-2 vaccine responses, in vivo and in vitro, Molecular and Cellular Immunobiology
OpenAlex ID: W2073726802