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Ref Type Journal Article
PMID (32956452)
Authors Pastore F, Krishnan A, Hammarén HM, Silvennoinen O, Yan B, Levine RL
Title JAK2S523L, a novel gain-of-function mutation in a critical autoregulatory residue in JAK2V617F- MPNs.
Journal Vol Issue Date Pages Journal Short Title
Blood advances 4 18 2020 Sep 22 4554-4559 Blood Adv
URL
Abstract Text The SH2-JH2 linker domain of JAK2 has been implicated in the negative regulation of JAK2 activity. In 2 patients with myeloproliferative neoplasms (MPNs), we identified and characterized the novel JAK2 mutation S523L, which occurs in a key residue in the linker region. In 1 case, acquisition of JAK2S523L was associated with thrombocytosis and bone marrow megakaryocytic hyperplasia, and there were no other somatic alterations in this patient. The second patient with JAK2S523Lmutation presented with increased hematocrit and had concurrent mutations in RUNX1 and BCORL1. Consistent with the genetic and clinical data, expression of JAK2S523L causes interleukin-3-independent growth in Ba/F3 cells transduced with the erythropoietin receptor by constitutively active Jak2/Stat5 signaling.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK2 S523L missense gain of function JAK2 S523L lies within a linker region of the Jak2 protein (PMID: 29685781). S523L results in impaired phosphorylation of Jak2 at S523, a site that negatively regulates Jak2 activity, and demonstrates increased cytokine-independent phosphorylation of Jak2 and Stat5 and cytokine-independent growth in cell culture (PMID: 32956452).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References